Topical pharmaceutical compositions

ABSTRACT

The present invention relates to topical pharmaceutical emulsion compositions comprising a therapeutically effective amount of 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, a water phase, a surfactant, and an antioxidant, and wherein the emulsion composition is homogeneous and/or the active is solubilized in the oil phase. The invention also relates to methods of treating a dermatological condition or disorder in a patient by administering the present compositions to the skin of the patient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.16/255,121 filed Jan. 23, 2019, which is a divisional of U.S. patentapplication Ser. No. 15/158,858 filed May 19, 2016, which claims thebenefit of U.S. Provisional Application No. 62/165,097 filed May 21,2015 and U.S. Provisional Application No. 62/324,450 filed Apr. 19,2016, each of which are hereby incorporated by reference in theirentirety.

FIELD OF THE INVENTION

The present invention relates to topical pharmaceutical compositions.

BACKGROUND OF THE INVENTION

A challenge for the formulation chemist is to prepare a physicallystable topical pharmaceutical composition where the active ingredient isalso found to be chemically stable. Such pharmaceutical compositionsshould:

-   -   (i) not irritate the skin,    -   (ii) be specifically adapted to deliver the active ingredient        onto or into the skin so as to treat a particular dermatological        condition or disorder,    -   (iii) be cosmetically elegant to ensure that the patient        complies with the prescribed treatment regimen,    -   (iv) provide penetration of the active ingredient to the        appropriate layers of the skin and engage the desired target,        and    -   (v) minimize systemic exposure while achieving local        dermal/epidermal delivery.

One active ingredient of interest to be formulated in a physically andchemically stable topical composition is3,5-Dihydroxy-4-isopropyl-trans-stilbene which has the followingformula:

This compound is also known as5-[(E)-2-phenylethenyl]-2-(propan-2-yl)benzene-1,3-diol or2-(1-Methyethyl)-5-[(1E)-2-phenylethenyl]-1,3-benzenediol.

3,5-Dihydroxy-4-isopropyl-trans-stilbene is believed to have beenoriginally disclosed by Paul et al., Journal of Chemical Ecology 19817(3): 589-597 as an antibiotic. Li et al, Applied and EnvironmentalMicrobiology 1995 61(12): 4329-4333 also isolated the compound, but froma different bacterial strain and further demonstrated its fungicidalactivity. The fungicidal activity of the compound was also described inWO 1995/003695 (Agro-Biotech Corporation). The compound is furtherdescribed in WO 2001/042231 (Welichem Biotech Inc.) and in U.S. Pat. No.7,868,047 and as being suitable for the treatment of various keydermatological conditions including psoriasis and inflammation. Example3 of the U.S. Pat. No. 7,868,047 describes a cream formulation with anactive ingredient being made in Galax Base. Applicants have been unableto ascertain any compendial notations or availability of a commercialcream base called “Galax” and therefore its composition remains unknown.

3,5-Dihydroxy-4-isopropyl-trans-stilbene is known to be sensitive tooxidation and photo degradation (see e.g. Gao et al., Journal of PolymerResearch 2011 18: 1501-1508). Accordingly, there remains a need in theart for a topical composition comprising3,5-Dihydroxy-4-isopropyl-trans-stilbene that is both chemically andphysically stable, which delivers the active ingredient to the desiredsite of action in the epidermis and/or dermis, and which does notirritate the skin in use.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the appearance of a non-uniform emulsion that wascharacteristic of Formulations 2-14.

FIG. 2 illustrates the appearance of a non-uniform emulsion that wascharacteristic of Formulations 2-14 compared with the physically stableformulation characterized by Formulation 15-40.

FIG. 3 illustrates the amount of3,5-Dihydroxy-4-isopropyl-trans-stilbene delivered into the epidermisand dermis from Formulations 1, 12, 17 and 21-24.

FIG. 4 illustrates the amount of3,5-Dihydroxy-4-isopropyl-trans-stilbene delivered into the receivingfluid over 15 hours from Formulations 1, 12, 17, and 21-24.

FIG. 5 illustrates the amount of3,5-Dihydroxy-4-isopropyl-trans-stilbene delivered into the dermis at 3,6, 9, 12 and 15 hours from Formulations 12 and 21.

FIG. 6 illustrates the amount of3,5-Dihydroxy-4-isopropyl-trans-stilbene delivered into the receivingfluid over 72 hours from Formulations 12 and 21.

FIG. 7 illustrates the percent change of mRNA Cyp1A1 in human ex vivoskin after Thl7 stimulation from Formulations 12, 17, 21 and 22.

FIG. 8 illustrates the amount of3,5-Dihydroxy-4-isopropyl-trans-stilbene delivered into skin ofGottingen minipigs after 7 days of repeat dosing.

FIG. 9 illustrates the amount of3,5-Dihydroxy-4-isopropyl-trans-stilbene in the plasma of Gottingenminipigs after 7 days of repeat dosing. As noted herein, “Formulation 12(2.0%)” as used throughout, including FIGS. 8 and 9 corresponds toFormulation 14.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides for a topicalpharmaceutical emulsion composition comprising the active ingredient3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant, andan antioxidant, and wherein the emulsion composition is homogeneous.

In another embodiment, the active is solubilized in the oil phase of theemulsion composition. In another embodiment, if the oil phase containsmineral oil or petrolatum, then a second oil phase component is present,and if the oil phase contains both mineral oil and petrolatum than athird oil phase component is present. In one embodiment, the oil phaseis substantially free from petrolatum. In another embodiment, the oilphase contains ≤3%, or ≤2%, or ≤1% petrolatum. In another embodiment, ifthe oil phase contains both mineral oil and petrolatum at least a thirdoil phase component is present which is an ester or an ester ofglycerin, suitably an ester of glycerin such as a medium chaintriglyceride. In another embodiment, if the oil phase contains mineraloil then a second oil phase component is present which is an ester or anester of glycerin, suitably an ester of glycerin such as a medium chaintriglyceride.

In one embodiment, the present invention provides for a topicalpharmaceutical emulsion composition comprising an effective amount ofthe active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or apharmaceutically acceptable salt thereof, an oil phase, a water phase, asurfactant, and an antioxidant, wherein the emulsion composition ishomogeneous and the 3,5-Dihydroxy-4-isopropyl-trans-stilbene orpharmaceutically acceptable salt thereof is solubilized in the oil phaseof the emulsion composition, and provided that if the oil phase containsmineral oil or petrolatum, then a second oil phase component is present,and if the oil phase contains both mineral oil and petrolatum then athird oil phase component is present. In one embodiment, the oil phaseis substantially free from petrolatum. In another embodiment, the oilphase contains ≤3%, or ≤2%, or ≤1% petrolatum. In another embodiment, ifthe oil phase contains both mineral oil and petrolatum at least a thirdoil phase component is present which is an ester and/or and ester ofglycerin, suitably an ester of glycerin, such as a medium chaintriglyceride. In another embodiment, if the oil phase contains mineraloil then a second oil phase component is present which is an esterand/or an ester of glycerin, suitably an ester of glycerin, such as amedium chain triglyceride.

In one embodiment, the present invention provides for a topicalpharmaceutical emulsion composition comprising the active ingredient3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant, andan antioxidant, and wherein the active is solubilized in the oil phaseof the emulsion composition. In another embodiment, the emulsioncomposition is homogeneous.

In another embodiment, the present invention provides for a topicalpharmaceutical emulsion composition comprising the active ingredient3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant, andan antioxidant, and wherein the emulsion composition is homogeneousand/or the active is solubilized in the oil phase of the emulsioncomposition.

In another embodiment, the present invention provides for a topicalpharmaceutical emulsion composition comprising the active ingredient3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant, andan antioxidant, and wherein the average the average droplet size of thediscontinuous phase is less than about 35 microns. In anotherembodiment, the average the average droplet size of the discontinuousphase is less than about 25 microns. In another embodiment, the averagethe average droplet size of the discontinuous phase is less than about15 microns. In another embodiment, the average droplet size of thediscontinuous phase is less than about 10 microns. In anotherembodiment, the average droplet size of the discontinuous phase is lessthan about 5 microns. In another embodiment, the average droplet size ofthe discontinuous phase is about or is less than about 1 micron. Inanother embodiment, the average droplet size of the discontinuous phaseis from about about 0.05 to about 1 micron. In another embodiment, theaverage droplet size of the discontinuous phase is from about 0.1 toabout 0.75 microns. In another embodiment, the average droplet size ofthe discontinuous phase is about 0.5 microns.

In another embodiment, the present invention provides for a topicalpharmaceutical emulsion composition comprising the active ingredient3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant, andan antioxidant, and wherein the average particle size of the oil phaseis less than about 10 microns, and the emulsion composition ishomogeneous and/or the active is solubilized in the oil phase of theemulsion composition.

In another embodiment, the invention provides a method of treating adermatological condition or disorder in a patient in need thereof, themethod comprising administering to said patient a topical pharmaceuticalemulsion composition comprising the active ingredient3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant, andan antioxidant, and wherein the emulsion composition is homogeneous. Inanother embodiment, the active is solubilized in the oil phase of theemulsion composition. In another embodiment, if the oil phase containsmineral oil or petrolatum, then a second oil phase component is present,and if the oil phase contains both mineral oil and petrolatum than athird oil phase component is present. In one embodiment, the oil phaseis substantially free from petrolatum. In another embodiment, the oilphase contains ≤3%, or ≤2%, or ≤1% petrolatum. In another embodiment, ifthe oil phase contains both mineral oil and petrolatum at least a thirdoil phase component is present which is an ester or an ester ofglycerin, suitably an ester of glycerin such as a medium chaintriglyceride. In another embodiment, if the oil phase contains mineraloil then a second oil phase component is present which is an ester or anester of glycerin, suitably an ester of glycerin such as a medium chaintriglyceride.

In another embodiment, the invention provides a method of treating adermatological condition or disorder in a patient in need thereof, themethod comprising administering to said patient a topical pharmaceuticalemulsion composition comprising an effective amount of the activeingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or apharmaceutically acceptable salt thereof, an oil phase, a water phase, asurfactant, and an antioxidant, wherein the3,5-Dihydroxy-4-isopropyl-trans-stilbene or pharmaceutically acceptablesalt thereof is solubilized in the oil phase of the emulsioncomposition, and provided that if the oil phase contains mineral oil orpetrolatum, then a second oil phase component is present, and if the oilphase contains both mineral oil and petrolatum than a third oil phasecomponent is present. In one embodiment, the oil phase is substantiallyfree from petrolatum. In another embodiment, the oil phase contains ≤3%,or ≤2%, or ≤1% petrolatum. In another embodiment, if the oil phasecontains both mineral oil and petrolatum then at least a third oil phasecomponent is present which comprises an ester and/or an ester ofglycerin, suitably an ester of glycerin, such as a medium chaintriglyceride. In another embodiment, if the oil phase contains mineraloil then a second oil phase component is present which is an esterand/or an ester of glycerin, suitably an ester of glycerin, such as amedium chain triglyceride. In one embodiment, the dermatologicalcondition or disorder is an inflammatory dermatological condition ordisorder. In another embodiment, the inflammatory dermatologicalcondition or disorder is atopic dermatitis and/or psoriasis, and/oracne.

In another embodiment, the invention relates to the use of a topicalpharmaceutical emulsion composition comprising an effective amount ofthe active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or apharmaceutically acceptable salt thereof, an oil phase, a water phase, asurfactant, and an antioxidant, and wherein the emulsion is homogenous,for use in the treatment or prophylaxis of a dermatological condition ordisorder in a human patient.

In another embodiment, the invention relates to the use of a topicalpharmaceutical emulsion composition comprising an effective amount ofthe active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or apharmaceutically acceptable salt thereof, an oil phase, a water phase, asurfactant, and an antioxidant, wherein the3,5-Dihydroxy-4-isopropyl-trans-stilbene or pharmaceutically acceptablesalt thereof is solubilized in the oil phase of the emulsioncomposition, and provided that if the oil phase comprises mineral oil orpetrolatum, then a second oil phase component is present, and if the oilphase contains both mineral oil and petrolatum than a third oil phasecomponent is present. In one embodiment, the oil phase is substantiallyfree from petrolatum. In another embodiment the oil phase contains ≤3%,or ≤2%, or ≤1% petrolatum. In another embodiment, if the oil phasecontains both mineral oil and petrolatum at least a third oil phasecomponent is present which is an ester and/or an ester of glycerin,suitably an ester of glycerin such as a medium chain triglyceride. Inanother embodiment, if the oil phase contains mineral oil then a secondoil phase component is present which is an ester and/or an ester ofglycerin, suitably an ester of glycerin, such as a medium chaintriglyceride.

In another embodiment, the invention relates to a topical pharmaceuticalemulsion composition comprising an effective amount of the activeingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or apharmaceutically acceptable salt thereof, an oil phase, a water phase, asurfactant, and an antioxidant, wherein the3,5-Dihydroxy-4-isopropyl-trans-stilbene or pharmaceutically acceptablesalt thereof is solubilized in the oil phase of the emulsioncomposition, and provided that if the oil phase contains mineral oil orpetrolatum, then a second oil phase component is present, and if the oilphase contains both mineral oil and petrolatum than a third oil phasecomponent is present for use in the treatment or prophylaxis of adermatological condition or disorder in a human patient. In oneembodiment, the oil phase is substantially free from petrolatum. Inanother embodiment, the oil phase contains ≤3%, or ≤2%, or ≤1%petrolatum. In another embodiment, if the oil phase contains bothmineral oil and petrolatum at least a third oil phase component ispresent which is an ester and/or an ester of glycerin, suitably an esterof glycerin such as a medium chain triglyceride. In another embodiment,if the oil phase contains mineral oil then a second oil phase componentis present which is an ester and/or and ester of glycerin, suitably anester of glycerin, such as a medium chain triglyceride.

In another embodiment, the invention relates to a method of reducingirritancy in a topical pharmaceutical emulsion composition containingthe active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or apharmaceutically acceptable salt thereof in use in a patient in needthereof, the method comprising administering to the patient apharmaceutical emulsion composition comprising an oil phase, a waterphase, a surfactant, and an antioxidant, wherein the3,5-Dihydroxy-4-isopropyl-trans-stilbene or pharmaceutically acceptablesalt thereof is solubilized in the oil phase of the emulsioncomposition, and provided that if the oil phase contains mineral oil orpetrolatum, then a second oil phase component is present, and if the oilphase contains both mineral oil and petrolatum than a third oil phasecomponent is present. In one embodiment, the oil phase is substantiallyfree from petrolatum. In another embodiment the oil phase contains ≤3%,or ≤2%, or ≤1% petrolatum. In another embodiment, if the oil phasecontains both mineral oil and petrolatum at least a third oil phasecomponent is present which is an ester and/or an ester of glycerin,suitably an ester of glycerin, such as a medium chain triglyceride. Inanother embodiment, if the oil phase contains mineral oil then a secondoil phase component is present which is an ester and/or an ester ofglycerin, suitably an ester of glycerin such as a medium chaintriglyceride.

In one embodiment, the emulsion composition of the instant invention iscompared to that of Formulation 1 or 12 (with comparable % w/w active).

In another embodiment, the invention relates to a method of improvingthe residency time of the active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable saltthereof in the skin of a patient in need thereof, the method comprisingadministering to said patient a pharmaceutical emulsion compositioncomprising an effective amount of3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant, andan antioxidant, wherein the emulsion composition is homogenous.

In another embodiment, the invention relates to a method of improvingthe residency time of the active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable saltthereof in the skin of a patient in need thereof, the method comprisingadministering to said patient a pharmaceutical emulsion compositioncomprising an effective amount of3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant, andan antioxidant, wherein the 3,5-Dihydroxy-4-isopropyl-trans-stilbene orpharmaceutically acceptable salt thereof is solubilized in the oil phaseof the emulsion composition, and provided that if the oil phase containsmineral oil or petrolatum, then a second oil phase component is present,and if the oil phase contains both mineral oil and petrolatum than athird oil phase component is present. In one embodiment, the oil phaseis substantially free from petrolatum. In another embodiment the oilphase contains ≤3%, or ≤2%, or ≤1% petrolatum. In another embodiment, ifthe oil phase contains both mineral oil and petrolatum at least a thirdoil phase component is present which is an ester and/or an ester ofglycerin, suitably an ester of glycerin such as a medium chaintriglyceride. In another embodiment, if the oil phase contains mineraloil then a second oil phase component is present which is which is anester and/or an ester of glycerin, suitably an ester of glycerin such asa medium chain triglyceride. In one embodiment, the emulsion compositionof the instant invention is compared to that of the Formulation 1 or 12(with comparable % w/w of active ingredient).

In another embodiment, the invention relates to a method of improvingthe residency time of the active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable saltthereof in the skin of a patient in need thereof, the method comprisingadministering to said patient a pharmaceutical emulsion compositioncomprising an effective amount of3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant, andan antioxidant, and wherein the emulsion is homogeneous and/or theactive is solubilized in the oil phase. In another embodiment, theaverage droplet size of the discontinuous phase is about 5 micron orless. In another embodiment, the average droplet size of thediscontinuous phase is about 1 micron or less.

In another embodiment, the invention relates to a method of reducingside effects in a patient who is administered a composition containing3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, the method comprising administering to thepatient a pharmaceutical emulsion composition comprising an oil phase, awater phase, a surfactant, and an antioxidant, and wherein the emulsionis homogenous and/or the active is solubilized in the oil phase. Inanother embodiment, the average droplet size of the discontinuous phaseis about 5 micron or less. In another embodiment, the average dropletsize of the discontinuous phase is about 1 micron or less

In another embodiment, the invention relates to a method of reducingside effects in a patient who is administered a composition containing3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, the method comprising administering to thepatient a pharmaceutical emulsion composition comprising an oil phase, awater phase, a surfactant, and an antioxidant, and wherein the3,5-Dihydroxy-4-isopropyl-trans-stilbene or pharmaceutically acceptablesalt thereof is solubilized in the oil phase of the emulsioncomposition, and provided that if the oil phase contains mineral oil orpetrolatum, then a second oil phase component is present, and if the oilphase contains both mineral oil and petrolatum than a third oil phasecomponent is present. In one embodiment, the oil phase is substantiallyfree from petrolatum. In another embodiment the oil phase contains ≤3%,or ≤2%, or ≤1% petrolatum. In another embodiment, if the oil phasecontains both mineral oil and petrolatum at least a third oil phasecomponent is present which is an ester and/or and ester of glycerin,suitably an ester of glycerin such as a medium chain triglyceride. Inanother embodiment, if the oil phase contains mineral oil then a secondoil phase component is present which is an ester and/or and ester ofglycerin, suitably an ester of glycerin such as a medium chaintriglyceride. In one embodiment, the emulsion composition of the instantinvention is compared to that of Formulation 1 or 12, or a similarformulation with equivalent active ingredient present.

In one embodiment, the present invention provides for a topicalpharmaceutical emulsion composition comprising an effective amount of3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant, andan antioxidant, wherein the 3,5-Dihydroxy-4-isopropyl-trans-stilbene orpharmaceutically acceptable salt thereof is solubilized in the oil phaseof the emulsion composition, and wherein if the oil phase containsmineral oil, then a second oil phase component other than petrolatum ispresent in the composition.

In an embodiment, the invention provides for a topical pharmaceuticalemulsion composition comprising 3,5-Dihydroxy-4-isopropyl-trans-stilbeneor a pharmaceutically acceptable salt thereof, an oil phase, a waterphase, a surfactant, and an antioxidant, wherein the3,5-Dihydroxy-4-isopropyl-trans-stilbene or pharmaceutically acceptablesalt thereof is solubilized in the oil phase of the emulsioncomposition, and wherein if the oil phase contains mineral oil then asecond oil phase component other than petrolatum is present in thecomposition, or if the oil phase contains both mineral oil andpetrolatum at least a third oil phase component is present. In anotherembodiment, the oil phase is substantially free from mineral oil and/orpetrolatum.

DETAILED DESCRIPTION OF THE INVENTION

In addition to creating a physically and chemically stablepharmaceutical formulation, the present invention also provides for apharmaceutical formulation which is non-irritating to the skin uponapplication and use, or is one which is less irritating than anyprevious formulations used in the development of the active ingredientto date. Another aspect of the invention is a formulation that not onlyhas superior skin penetration and target engagement of the appropriatereceptors, but also has significant non-systemic exposure of the activeingredient to the patient upon application and use.

In an embodiment, the invention provides for a topical pharmaceuticalemulsion composition comprising the active ingredient3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant, andan antioxidant, and wherein the emulsion composition is homogenous. Inone embodiment, the 3,5-Dihydroxy-4-isopropyl-trans-stilbene orpharmaceutically acceptable salt thereof is solubilized in the oil phaseof the emulsion composition. In another embodiment, if the oil phasecontains mineral oil or petrolatum, then a second oil phase component ispresent, and if the oil phase contains both mineral oil and petrolatumthan a third oil phase component is present. In one embodiment, the oilphase is substantially free from petrolatum. In another embodiment, theoil phase contains ≤3%, or ≤2%, or ≤1% petrolatum. In anotherembodiment, if the oil phase contains both mineral oil and petrolatumthen at least a third oil phase component is present which is an esterand/or an ester of glycerin, suitably an ester of glycerin, such as amedium chain triglyceride. In another embodiment, if the oil phasecontains mineral oil, then a second oil phase component is present whichis an ester and/or an ester of glycerin, suitably an ester of glycerin,such as a medium chain triglyceride. The second oil phase component andthe third oil phase component are used as co-solvents for the activeingredient in the oil phase of the emulsion composition. That is, thesecond and third oil phase components act as oil miscible co-solvents.

In one embodiment, the amount of the active ingredient solubilized inthe oil phase of the emulsion composition is present in an amount of≥50% w/w, or ≥60% w/w, or ≥70% w/w, or ≥80% w/w, or ≥90% w/w or ≥95% w/wor ≥98% w/w, based on the percent by weight of the active ingredient. Ina preferred embodiment ≥95% or ≥98% w/w of the active ingredient issolubilized in the oil phase of the emulsion, producing a homogenouscomposition.

In an alternative embodiment, the3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof is solubilized in the water phase of theemulsion composition. Since 3,5-Dihydroxy-4-isopropyl-trans-stilbene isnot soluble in water, a water miscible organic solvent (i.e. a watermiscible co-solvent) may used to solublize the active ingredient in thewater phase of the emulsion. Suitably, the active ingredient solubilizedin the water phase of the emulsion composition is present in an amount≥10% w/w, or ≥20% w/w, or ≥30% w/w, or ≥40% w/w, or ≥50% w/w, or ≥60%w/w, or ≥70% w/w, or ≥80% w/w, or ≥90% w/w or ≥95% w/w, based on thepercent by weight of the active ingredient.

When used herein, the term “D90” refers to the oil droplet size diameterof which 90% of the droplets are less than a particular size.Alternatively, the term “D90” is defined as the size in microns belowwhich 90 percent of the oil droplets reside on a volume basis. In anembodiment, the D90 of the average droplet size of the discontinuousphase in the composition is less than 15 microns. In another embodiment,the average droplet size of the discontinuous phase according to thepresent invention have a D90 of less than 5 microns.

When used herein, the term “D50” refers to the median or 50^(th)percentile of which the droplets are less than a particular size.Alternatively, the term “D50” is defined as the size in microns belowwhich 50 percent of the oil droplets reside on a volume basis. In anembodiment, the D50 of the average droplet size of the discontinuousphase in the composition is less than 5 microns. In another embodiment,the average droplet size of the discontinuous phase according to thepresent invention have a D50 of less than 1 micron.

Methods for measuring oil droplet size distribution are well known inthe art. In one embodiment, oil droplet size diameter distribution oildroplet size in the composition according to the present invention maybe measured using a laser diffraction techniques. Suitable laserdiffraction apparatus include, for example, the Sympatec HELOS/QUIXEL,or the Malvern Laser Diffractonamer obtainable from Malvern Instruments,Malvern, UK as well as others.

In one embodiment, the present invention provides for a topicalpharmaceutical emulsion composition comprising the active ingredient3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant, andan antioxidant, and wherein the average droplet size of thediscontinuous phase is less than about 35 microns. In anotherembodiment, the average droplet size of the discontinuous phase is lessthan about 25 microns. In another embodiment, the average droplet sizeof the discontinuous phase is less than about 15 microns. In anotherembodiment, the average droplet size of the discontinuous phase is lessthan about 10 microns. In another embodiment, the average droplet sizeof the discontinuous phase is less than about 5 microns. In anotherembodiment, the average droplet size of the discontinuous phase is aboutor is less than about 1 micron. In another embodiment, the averagedroplet size of the discontinuous phase is from about 0.05 to about 35microns. In another embodiment, the average droplet size of thediscontinuous phase is from about about 0.05 to about 5 micron. Inanother embodiment, the average droplet size of the discontinuous phaseis from about about 0.05 to about 1 micron. In another embodiment, theaverage droplet size of the discontinuous phase is from about 0.1 toabout 0.75 microns.

In one embodiment, at least 90% of the droplets in the oil phase of theoil-in-water emulsion (e.g. the discontinuous phase) have a droplet sizeof about or less than 1 micron. In another embodiment at least 95, 97,98, or 99% of the droplets are about or less than 1 micron.

Alternatively, or at least in addition to, at least about 75%, or atleast about 85%, or at least about 90%, of the droplet size of thediscontinuous phase oil in the oil-in-water emulsion have a size of lessabout 10 microns, or less that about 5 microns or less than about 1micron, or less than about 0.75 microns. Any combination of the abovepercentages and droplet sizes may be used to define oil droplets in acomposition of the present invention.

In one embodiment, the emulsion composition of the present inventionsuitably have at least one of the following characteristics: a D50 ofmean droplet diameter of less than 1 micron when measured at 2-8 degreesC.°; and/or when measured at 25 degrees C.° and 60% RH, and/or whenmeasured at 30 degrees C.° at 6 months; or both a D50 mean dropletdiameter of less than 1 micron when measured at 30 degrees C.° at 6months.

In another embodiment, a topical pharmaceutical emulsion compositioncomprising the active ingredient3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant, andan antioxidant, and wherein the average droplet size of the oil phase isless than about 5 microns and optionally the emulsion is homogenous. Inanother embodiment the active is solubilized in the oil phase.

In another embodiment, a topical pharmaceutical emulsion compositioncomprising the active ingredient3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant, andan antioxidant, and wherein the average droplet size of the oil phase isless than about 1 micron and optionally the emulsion is homogenous. Inanother embodiment the active is solubilized in the oil phase.

The terms “emulsion” and “oil-in-water emulsion” as used herein, andunless otherwise stated or understood from the context used, refers to acolloidal dispersion system in which liquid oil is dispersed as droplets(the discrete phase, also referred to as “the discontinuous non-aqueousphase” or “the discontinuous phase”) in an continuous aqueous medium(the continuous phase, also referred to as “the continuous aqueousphase” or “the continuous phase”). In some embodiments, at least 50% ofthe active ingredient (w/w) is dissolved and remains in the emulsion. Insome embodiments, at least 75% of the active ingredient (w/w) isdissolved and remains in the emulsion. In certain embodiments, as isfurther described herein, greater than 85% of the active ingredient ispresent in the discontinuous phase.

3.5-Dihydroxy-4-isopropyl-trans-stilbene

In an embodiment, the 3,5-Dihydroxy-4-isopropyl-trans-stilbene or apharmaceutically acceptable salt thereof is present in the emulsioncomposition in an amount from about 0.01% to about 5% by weight, such asfrom about 0.05% to about 2% by weight, based on the total weight of thecomposition. In another embodiment, the3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof is present in an amount from about 0.1% to about1.0% by weight, based on the total weight of the composition. In anembodiment, the 3.5-Dihydroxy-4-isopropyl-trans-stilbene or apharmaceutically acceptable salt thereof is present in an amount ofabout 0.25%, 0.30%, 0.40%, 0.50%, 0.75%, 1% or 2% by weight, based onthe total weight of the composition. In one embodiment, the3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof is present in an amount of about 0.25% to about0.50% by weight.

Oil Phase

The present topical pharmaceutical emulsion compositions comprise an oilphase. Suitably, the oil phase comprises one or more oils and/or fats.

Exemplary oils and fats include fatty acids, esters, esters of glycerin,fatty alcohols, waxes, sterols, unsaponifiables, siloxanes, silanes,lanolin, hydrocarbons, essential oils, vegetable oils, mineral oils,animal oils and edible oils, and mixtures thereof.

In an embodiment, the oil and/or fat is selected from the groupconsisting of an ester and an ester of glycerin, and mixtures thereof.In another embodiment, the oil and/or fat is at least an ester ofglycerin.

In an embodiment, the oil phase comprises a fatty acid. Exemplary fattyacids include, but are not limited to, isostearic acid, oleic acid,stearic acid, linoleic acid, linolenic acid, myristic acid, palmiticacid, ricinoleic acid and arachidic acid, and mixtures thereof.

In an embodiment, the oil phase comprises an ester. Exemplary estersinclude, but are not limited to, coco-caprylate/caprate, diethylsebacate, diisopropyl adipate, diisopropyl dilinoleate, ethyl oleate,ethylhexyl hydroxystearate, glycol distearate, glycol stearate,hydroxyoctacosanyl hydroxystearate, isopropyl isostearate, isopropylmyristate, isopropyl palmitate, isopropyl stearate, methyl glucosesesquistearate, methyl laurate, methyl salicylate, methyl stearate,myristyl lactate, octyl salicylate, oleyl oleate, PPG-20 methyl glucoseether distearate, propylene glycol diacetate, propylene glycoldicaprylate, propylene glycol monolaurate, propylene glycolmonopalmitostearate, propylene glycol ricinoleate, triacetin and sucrosedistearate, and mixtures thereof. In one embodiment, the ester isdiethyl sebacate or diisopropyl adipate.

In an embodiment, the oil phase comprises an ester of glycerin.Exemplary esters of glycerin include, but are not limited to,caprylic/capric glycerides, caprylic/capric triglyceride,caprylic/capric/succinic triglyceride, capryl glucoside, cetearylglucoside, cocoglycerides, decyl glucoside, lauryl glucoside, glycerylcitrate, glyceryl isostearate, glyceryl laurate, glyceryl monostearate,glyceryl oleate, glyceryl palmitate, glyceryl ricinoleate, glycerylstearate, mono and diglyceride, PEG-12 glyceryl laurate, PEG-120glyceryl stearate, polyglyceryl-3 oleate, polyoxyl glyceryl stearate,tallow glycerides and medium chain triglycerides (MCT), and mixturesthereof. In one embodiment, the oil phase of the emulsion comprisesmedium chain triglycerides. In one embodiment, the medium chaintriglyceride carbon length is from C6 to C12. In another embodiment, themedium chain triglyceride carbon length is from C6 to C8.

In an embodiment, the oil phase comprises a fatty alcohol. Exemplaryfatty alcohols include, but are not limited to, caprylic alcohol, decylalcohol, lauryl alcohol, myristyl alcohol, behenyl alcohol, lanolinalcohol, arachidyl alcohol, oleyl alcohol, palm alcohol, isocetylalcohol, cetyl alcohol and stearyl alcohol, mixtures thereof. In oneembodiment, the fatty alcohol is a mixture of cetyl alcohol and stearylalcohol. Suitably, the ratio of cetyl alcohol to stearyl alcohol isabout 2:1 to about 1:9.

In an embodiment, the oil phase comprises a wax. Exemplary waxesinclude, but are not limited to, beeswax, carnauba wax, dimethiconePEG-1 beeswax, dimethiconol beeswax, lanolin wax, microcrystalline wax,white wax, candelilla wax, paraffin wax, emulsifying wax, PEG-8 beeswax,yellow wax, cetyl esters wax, shellac wax and synthetic beeswax, andmixtures thereof.

In an embodiment, the oil phase comprises a sterol. Exemplary sterolsinclude, but are not limited to, Brassica campestris sterols, C₁₀-C₃₀cholesterol/lanosterol esters, canola sterols, cholesterol, lanolincholesterols, glycine soja sterols, PEG-20 phytosterol and phytosterols,and mixtures thereof.

In an embodiment, the oil phase comprises a siloxane and/or silane.Exemplary siloxanes and silanes include, but are not limited to,dimethicone, cyclomethicone, simethicone, phenyl dimethicone,cyclopentasiloxane, cyclotetrasiloxane, dimethyl siloxane anddimethicone cross polymer, and mixtures thereof.

In an embodiment, the oil phase comprises a hydrocarbon. Exemplaryhydrocarbons include, but are not limited to, dodecane, petrolatum,squalane, squalene and paraffin, and mixtures thereof.

In an embodiment, the oil phase comprises an essential oil. Exemplaryessential oils include, but are not limited to, primrose oil, rose oil,eucalyptus oil, borage oil, bergamot oil, chamomile oil, citronella oil,lavender oil, peppermint oil, pine oil, pine needle oil, spearmint oil,tea tree oil and wintergreen oil, and mixtures thereof.

In an embodiment, the oil phase comprises a vegetable oil. Exemplaryvegetable oils include, but are not limited to, almond oil, aniseed oil,canola oil, castor oil, coconut oil, corn oil, avocado oil, cottonseedoil, olive oil, palm kernel oil, peanut oil, sunflower oil, saffloweroil and soybean oil, and mixtures thereof.

In an embodiment, the oil phase may comprise a mineral oil. Exemplarymineral oils include, but are not limited to, mineral oil and lightmineral oil. If the oil phase comprises mineral oil, there is anotheroil phase component present in the formulation. In one embodiment, thesecond oil phase component will not be petrolatum. In one embodiment,the second oil phase component will not be a petrolatum derivative. Inone embodiment, the emulsion composition comprises an oil phase that issubstantially free from mineral oil. In another embodiment, the oilphase is substantially free from petrolatum. In another embodiment, theoil phase is substantially free from a petrolatum derivative. In anotherembodiment, the emulsion composition comprises an oil phase that issubstantially free from mineral oil and petrolatum. In anotherembodiment, the emulsion composition comprises an oil phase that issubstantially free from mineral oil, petrolatum and a petrolatumderivative.

In an embodiment, the oil phase comprises an edible oil. Exemplaryedible oils include, but are not limited to, cinnamon oil, clove oil,lemon oil and peppermint oil, and mixtures thereof.

In one embodiment, the oil phase of the emulsion comprises an ester ofglycerin which is a medium chain triglycerides (MCT). Suitably, the MCTis present in an amount from about 2% to about 30% by weight, based onthe total weight of the composition, such as about 2%, about 5%, about10%, about 15%, about 20%, about 25% or about 30% by weight, based onthe total weight of the composition. In another embodiment, the oilphase of the emulsion comprises MCT in an amount from about 5% to about30% by weight, based on the total weight of the composition. In anotherembodiment, the oil phase of the emulsion comprises MCT in an amountfrom about 5% to about 20% by weight, based on the total weight of thecomposition. In another embodiment, the MCT is present in an amount ofabout 10% by weight, based on the total weight of the composition.

In one embodiment, the oil phase comprises an oil and/or fat in anamount from about 5% to about 45% by weight, such as from about 5% toabout 35% by weight, based on the total weight of the composition. Inanother embodiment, the oil phase comprises an oil and/or fat in anamount from about 5% to about 25% by weight, based on the total weightof the composition. In yet another embodiment, the oil phase comprisesan oil and/or fat in an amount from about 5% to about 15% by weight,based on the total weight of the composition

Water Phase

The present topical pharmaceutical emulsion compositions comprise anaqueous or water phase comprising water. Suitably, the water is presentin the composition in an amount from about 25% to about 85% by weight,based on the total weight of the composition. In an embodiment, thewater is present in the composition in an amount from about 30% to about80% by weight, based on the total weight of the composition. In anotherembodiment, the water is present in an amount from about 55% to about75% by weight, based on the total weight of the composition.

Surfactant

The topical pharmaceutical emulsion compositions comprise a surfactant.In an embodiment, the surfactant is a mixture of two or moresurfactants. As used herein, a surfactant is a compound that lowers thesurface tension between two liquids or between a liquid and a solid.Surfactants may also act as detergents, wetting agents, emulsifiers,foaming agents, and dispersants. As further used herein, an emulsifieris equivalent to a surfactant.

Suitably, the surfactant is present in the composition in an amount fromabout 1% to about 20% by weight, such as from about 5% to about 15% byweight, based on the total weight of the composition.

A surfactant's hydrophilic/lipophilic balance (HLB) describes thesurfactant's affinity toward water or oil. The HLB scale ranges from 1(totally lipophilic) to 20 (totally hydrophilic), with 10 representingan equal balance of both characteristics. Lipophilic surfactants tend toform water-in-oil (w/o) emulsions, and hydrophilic surfactants tend toform oil-in-water (o/w) emulsions. The HLB of a blend of two surfactantsequals the weight fraction of surfactant A times its HLB value plus theweight fraction of surfactant B times its HLB value (weighted average).

In one embodiment, the surfactant comprises one or more non-ionicsurfactants. In another embodiment, the surfactant comprises two or morenon-ionic surfactants and the weighted average of the HLB values of thetwo or more non-ionic surfactants is from about 10 to about 20. In yetanother embodiment, the surfactant comprises two or more non-ionicsurfactants and the weighted average of the HLB values of the two ormore non-ionic surfactants is from about 1 to about 10.

Suitable non-ionic surfactants according to the invention include, butare not limited to, ethoxylated fatty alcohol ethers, PEG castor oils,PEG esters, propylene glycol esters, glyceryl esters and derivatives,polymeric ethers, sorbitan derivatives, fatty alcohols, emulsifyingwaxes, and mixtures thereof.

In an embodiment, the non-ionic surfactant is an ethoxylated fattyalcohol ether. Exemplary ethoxylated fatty alcohol ethers include, butare not limited to, steareth-2, steareth-10, steareth-20, steareth-21,steareth-40, steareth-100, beheneth-10, ceteareth-2, ceteareth-3,ceteareth-5, ceteareth-6, ceteareth-10, ceteareth-12, ceteareth-15,ceteareth-20, ceteareth-21, ceteareth-22, ceteareth-25, ceteareth-30,ceteareth-31, ceteareth-32, ceteareth-33, ceteth-2, ceteth-10,ceteth-20, ceteth-23, choleth-24, isoceteth-20, laureth-2, laureth-3,laureth-4, laureth-5, laureth-9, laureth-10, laureth-12, laureth-15,laureth-20, laureth-21, laureth-22, laureth-23, nonoxynol-9,nonoxynol-15, octoxynol-1, octoxynol-9, oleth-2, oleth-5, oleth-10,oleth-20, C20-40 pareth-24 and trideceth-10, and mixtures thereof.

In an embodiment, the non-ionic surfactant is a PEG castor oil.Exemplary PEG castor oils include, but are not limited to, PEG-7hydrogenated castor oil, PEG-25 hydrogenated castor oil, PEG-30 castoroil, PEG-33 castor oil, PEG-35 castor oil, PEG-36 castor oil, PEG-40castor oil, PEG-40 hydrogenated castor oil, PEG-50 castor oil, PEG-54hydrogenated castor oil, PEG-60 castor oil and PEG-60 hydrogenatedcastor oil, and mixtures thereof.

In an embodiment, the non-ionic surfactant is a PEG ester. Exemplary PEGesters include, but are not limited to, PEG-4 dilaurate, PEG-150distearate, PEG-12 glyceryl laurate, PEG-120 glyceryl stearate, PEG-6isostearate, PEG-4 laurate, PEG-8 laurate, PEG-20 methyl glucosesesquistearate, PEG-5 oleate, PEG-6 oleate, PEG-10 oleate, PEG-25propylene glycol stearate, PEG-2 stearate, PEG-6 stearate, PEG-6-32stearate, PEG-8 stearate, PEG-9 stearate, PEG-20 stearate, PEG-40stearate, PEG-45 stearate, PEG-50 stearate and PEG-100 stearate, andmixtures thereof.

In an embodiment, the non-ionic surfactant is a propylene glycol ester.Exemplary propylene glycol esters include, but are not limited to,propylene glycol laurate, propylene glycol palmitostearate, propyleneglycol ricinoleate and propylene glycol stearate, and mixtures thereof.

In an embodiment, the non-ionic surfactant is a glyceryl ester orderivative. Exemplary glyceryl esters and derivatives include, but arenot limited to, glyceryl behenate, glyceryl dibehenate, glyceryldioleate, glyceryl distearate, glyceryl isostearate, glyceryl laurate,glyceryl linoleate, glyceryl monostearate, glyceryl oleate, glycerylpalmitate, glyceryl ricinoleate, glyceryl stearate, PEG-23 glycerylcocoate, PEG-6 caprylic/capric glycerides, PEG-7 glyceryl cocoate,polyglyceryl-10 diisostearate, polyglyceryl-2 diisostearate,polyglyceryl-3 diisostearate and polyglyceryl-6 diisostearate, PEG-12glyceryl laurate, PEG-120 glyceryl stearate, and mixtures thereof.

In an embodiment, the non-ionic surfactant is a polymeric ether.Exemplary polymeric ethers include, but are not limited to, poloxamer124, poloxamer 181, poloxamer 182, poloxamer 184, poloxamer 188,poloxamer 237, poloxamer 331, poloxamer 338 and poloxamer 407, andmixtures thereof.

In an embodiment, the non-ionic surfactant is a sorbitan derivative.Exemplary sorbitan derivatives include, but are not limited to,polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65,polysorbate 80, sorbitan isostearate, sorbitan monolaurate, sorbitanmonooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitansesquioleate, sorbitan trioleate and sorbitan tristearate, and mixturesthereof.

In an embodiment, the non-ionic surfactant is a fatty alcohol. Exemplaryfatty alcohols include, but are not limited to, isostearyl alcohol,caprylyl alcohol, decyl alcohol, lauryl alcohol, myristyl alcohol,behenyl alcohol, lanolin alcohol, arachidyl alcohol, oleyl alcohol, palmalcohol, isocetyl alcohol, cetyl alcohol, stearyl alcohol and cetearylalcohol, and mixtures thereof. In one embodiment, the fatty alcohol is amixture of cetyl alcohol and stearyl alcohol, known as cetearyl alcohol(also known as cetostearyl alcohol).

In an embodiment, the non-ionic surfactant is an emulsifying wax, e.g. anon-ionic emulsifying wax also known as emulsifying wax NF, oremulsifying wax BP. In an embodiment, the emulsifying wax is a mixtureof cetearyl alcohol and polysorbate 60. In another embodiment, theemulsifying wax is a proprietary blend known as “Polawax NF”™ (CrodaInc, Edison, N.J., USA).

In one embodiment, the surfactant comprises one or more ethoxylatedfatty alcohol ethers. In another embodiment, the ethoxylated fattyalcohol ether is a mixture of steareth-2 and steareth-20.

In one embodiment, the surfactant comprises a mixture of an ethoxylatedfatty alcohol ether and a sorbitan derivative. In another embodiment,the mixture of an ethoxylated fatty alcohol ether and a sorbitanderivative is a mixture of steareth-2, steareth-20 and polysorbate 80.

In one embodiment, when there are 2 surfactants present in theformulation, each surfactant is present in an amount from about 0.5% toabout 5% by weight, based on the total weight of the composition. Inanother embodiment, when there are 3 surfactants present in theformulation, each surfactant is present in an amount from about 0.5% toabout 5% by weight, based on the total weight of the composition.Similarly, if there are 4 or more surfactants present they are eachpresent in an amount from about 0.5% to about 5% by weight, based on thetotal weight of the composition.

In one embodiment, the surfactant comprises a mixture of an ethoxylatedfatty alcohol ether and an emulsifying wax. In another embodiment, thesurfactant comprises a mixture of an ethoxylated fatty alcohol ether, asorbitan derivative and an emulsifying wax. Suitably, the mixture of anethoxylated fatty alcohol ether and an emulsifying wax is a mixture ofsteareth-2, steareth-20, and Polawax™ NF. Suitably, the mixture of anethoxylated fatty alcohol ether, a sorbitan derivative and anemulsifying wax is a mixture of steareth-2, steareth-20, polysorbate 80and Polawax™ NF. In an alternative embodiment, the surfactant comprisesa mixture of an ethoxylated fatty alcohol ether and a fatty alcohol.Suitably, the mixture of an ethoxylated fatty alcohol ether and a fattyalcohol is a mixture of steareth-2, steareth-20, and cetearyl alcohol.

In another embodiment, the surfactant comprises a mixture of anethoxylated fatty alcohol ether, a sorbitan derivative and a fattyalcohol. Suitably, the mixture of an ethoxylated fatty alcohol ether, asorbitan derivative and a fatty alcohol is a mixture of steareth-2,steareth-20, polysorbate 80 and cetearyl alcohol.

Antioxidant

The present topical pharmaceutical emulsion compositions comprise anantioxidant. In an embodiment, the antioxidant is a mixture of two ormore antioxidants.

Exemplary antioxidants include, but are not limited to, butylatedhydroxytoluene (BHT), butylated hydroxyanisole (BHA), tocopherol, propylgallate, vitamin E TPGS and tert-Butylhydroquinone (TBHQ), and mixturesthereof. In an embodiment, the antioxidant is selected from the groupconsisting of butylated hydroxytoluene, propyl gallate and tocopherol,and mixtures thereof.

In one embodiment, the antioxidant is butylated hydroxytoluene. Inanother embodiment, the antioxidant is propyl gallate. In yet anotherembodiment, the antioxidant is a mixture of butylated hydroxytoluene andpropyl gallate.

In an embodiment, the antioxidant is used in conjunction with achelating agent to prevent or minimize metal-catalyzed reactions, suchas reactions catalyzed by iron, nickel, copper, magnesium, calcium, zincor aluminum ions.

Suitably, the antioxidant is present in the composition in an amountfrom about 0.001% to about 5% by weight, based on the total weight ofthe composition. In an embodiment, the antioxidant is present in anamount from about 0.01% to 1% by weight, such as about 0.05% by weightor about 0.1% by weight, based on the total weight of the composition.

Dermatologically Acceptable Excipients

The present topical pharmaceutical emulsion compositions may furthercomprise one or more additional dermatologically acceptable excipients.Exemplary additional dermatologically acceptable excipients include, butare not limited to, a pH adjusting agent, a chelating agent, apreservative, a co-solvent, a penetration enhancer, a humectant, athickening or gelling or viscosity building agent, a fragrance, acolorant, and mixtures thereof.

In one embodiment, the additional dermatologically acceptable excipientis a preservative. In one embodiment, the additional dermatologicallyacceptable excipient is at least one co-solvent. In one embodiment, theadditional dermatologically acceptable excipient is selected from thegroup consisting of a pH adjusting agent, a chelating agent, apreservative and a co-solvent, and mixtures thereof. In anotherembodiment, the additional dermatologically acceptable excipientcomprises a mixture of a pH adjusting agent, a chelating agent, apreservative and a co-solvent.

In an embodiment, the emulsion is an oil-in-water emulsion. In anotherembodiment, the emulsion is a water-in-oil emulsion.

Suitably, the emulsion may be formulated as a cream. The cream may be anoil-in-water cream or a water-in-oil cream. In one particularembodiment, the cream is an oil-in-water cream.

In another embodiment, the emulsion may be formulated as a lotion. Thelotion may be an oil-in-water lotion or a water-in-oil lotion.

pH Adjusting Agent

The present topical pharmaceutical emulsion compositions may furthercomprise a pH adjusting agent.

In an embodiment, the pH adjusting agent is an acid, an acid salt, or amixture thereof. Suitably, the acid is selected from the groupconsisting of lactic acid, acetic acid, maleic acid, succinic acid,citric acid, benzoic acid, boric acid, sorbic acid, tartaric acid,edetic acid, phosphoric acid, nitric acid, sulphuric acid andhydrochloric acid, and mixtures thereof.

In another embodiment, the pH adjusting agent is a buffer. Suitably, thebuffer is selected from the group consisting of citrate/citric acid,acetate/acetic acid, phosphate/phosphoric acid, propionate/propionicacid, lactate/lactic acid, ammonium/ammonia and edetate/edetic acid. Inone embodiment, the pH adjusting agent is a buffer which iscitrate/citric acid.

Suitably, the pH adjusting agent is present in the composition in anamount from about 0.01% to about 10% by weight, based on the totalweight of the composition. In an embodiment, the pH of the compositionis adjusted with a pH adjusting agent to a pH of from about 4 to about7, such as from about 4.5 to about 6.5.

Chelating Agents

The present topical pharmaceutical emulsion compositions may furthercomprise a chelating agent. In an embodiment, the chelating agent is amixture of two or more chelating agents. As described herein, thecompositions of the invention may comprise a mixture of a chelatingagent and an antioxidant, where both excipients act to prevent orminimize oxidative degradation reactions in the composition.

Exemplary chelating agents include, but are not limited to, citric acid,glucuronic acid, sodium hexametaphosphate, zinc hexametaphosphate,ethylene diamine tetraacetic acid (EDTA), phosphonates, salts thereof,and mixtures thereof. Ethylene diamine tetraacetic acid is also known asedetic acid.

In one embodiment, the chelating agent is EDTA or a salt thereof, suchas potassium, sodium or calcium salts of EDTA. In an embodiment, theEDTA or a salt thereof is disodium EDTA. In another embodiment, thechelating agent is citric acid. In yet another embodiment, thecompositions of the invention comprise a mixture of a chelating agentand an antioxidant which is a mixture of EDTA or a salt thereof andpropyl gallate. In a further embodiment, the compositions of theinvention comprise a mixture of a chelating agent and an antioxidantwhich is a mixture of EDTA or a salt thereof and BHT. In one embodiment,the compositions of the invention comprise a mixture of a chelatingagent and an antioxidant which is a mixture of disodium EDTA and BHT.

In yet a further embodiment, the compositions comprise a mixture of achelating agent and an antioxidant which is a mixture of citric acid andpropyl gallate. In an embodiment, the compositions of the inventioncomprise a mixture of a chelating agent and an antioxidant which is amixture of citric acid and BHT.

Suitably, the chelating agent is present in the composition in an amountfrom about 0.01% to about 1% by weight, based on the total weight of thecomposition. In one embodiment, the chelating agent is present in thecomposition in an amount of about 0.1% by weight, based on the totalweight of the composition.

Preservatives

The present topical pharmaceutical emulsion compositions may furthercomprise a preservative. In an embodiment, the preservative is a mixtureof two or more preservatives.

Exemplary preservatives include, but are not limited to, benzyl alcohol,imidazolidinyl urea, diazolidinyl urea, dichlorobenzyl alcohol,chloroxylenol, methyl paraben, ethyl paraben, propyl paraben, butylparaben, phenoxyethanol, sorbic acid, benzoic acid, salts thereof, andmixtures thereof.

In an embodiment, the preservative is selected from the group consistingof benzyl alcohol, phenoxyethanol and benzoic acid, and mixturesthereof.

In one embodiment, the preservative is benzyl alcohol. In anotherembodiment, the preservative is phenoxyethanol. In yet anotherembodiment, the preservative is benzoic acid.

Suitably, the preservative is present in the composition in an amountfrom about 0.01% to about 2% by weight, based on the total weight of thecomposition. In one embodiment, the preservative is present in thecomposition in an amount of about 0.25% by weight, based on the totalweight of the composition.

Co-Solvent

The topical pharmaceutical emulsion compositions may further comprise aco-solvent. The function of the co-solvent is to help solubilize the3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof in the oil phase and/or the water phase of theemulsion composition, as desired. An oil miscible co-solvent may be usedto help solubilize the active ingredient in oil phase, and a watermiscible co-solvent may be used to help solubilize the active ingredientin the water phase. In one embodiment, the co-solvent is used to helpsolublize in the oil phase of the composition.

In an embodiment, the co-solvent is a mixture of two or moreco-solvents.

Exemplary co-solvents include, but are not limited to, alcohols such asethanol, isopropanol, t-butyl alcohol, amyl alcohol, benzyl alcohol,cyclohexanedimethanol, diacetone alcohol, hexyl alcohol,tetrahydrofurfuryl alcohol and diethylene glycol monoethyl ether;carboxylic acids such as acetic acid or multi carboxylic acid; diolssuch as 1,2-hexanediol, butylene glycol, diethylene glycol, dipropyleneglycol, ethyl hexanediol, ethylene glycol, hexylene glycol, pentyleneglycol, propylene glycol, propylene glycol monolaurate, tetraethyleneglycol, triethylene glycol, tripropylene glycol and polyethylene glycol;polyols such as butanetriol, glycerol and 1,2,6-hexanetriol; esters suchas butyl stearate, C12-15 alkyl benzoate, C12-15 alkyl lactate,caprylic/capric triglyceride, cetearyl ethylhexanoate, cetearylisononanoate, cetyl octanoate, cetyl palmitate, coco-caprylate/caprate,cocoglycerides, decyl oleate, dibutyl adipate, dicaprylyl carbonate,diethylhexyl adipate, di-ethylhexyl succinate, diisopropyl adipate,dioctyl malate, di-PPG-2 myreth-10 adipate, di-PPG-3 myristyl etheradipate, ethyl oleate, ethylhexyl cocoate, ethylhexyl hydroxystearate,ethylhexyl palmitate, ethylhexyl pelargonate, ethylhexyl stearate, hexyllaurate, hexyldecyl laurate, hexyldecyl stearate, isocetyl stearate,isocetyl stearoyl stearate, isodecyl oleate, isopropyl myristate,isopropyl palmitate, isostearyl neopentanoate, isotridecyl isononanoate,lauryl lactate, myristyl lactate, myristyl myristate, octyldodecylstearoyl stearate, oleyl erucate, oleyl oleate, pentaerythrityltetracaprylate/caprate, pentaerythrityl tetraisostearate, PPG-2 myristylether propionate, propylene glycol dicaprylate/dicaprate, propyleneglycol isostearate, propylheptyl caprylate, and stearyloctanoatedimethyl isosorbide and propylene carbonate.

In one embodiment, the co-solvent is propylene glycol. In anotherembodiment, the co-solvent is a mixture of propylene glycol anddiethylene glycol monoethyl ether.

Suitably, the co-solvent is present in the composition in an amount fromabout 1% to about 30% by weight, such as from about 5% to about 20% byweight, based on the total weight of the composition.

Penetration Enhancer

The present topical pharmaceutical emulsion compositions may furthercomprise a penetration enhancer. In an embodiment, the penetrationenhancer is a mixture of two or more penetration enhancers. Theco-solvent or mixture of two or more co-solvents described herein mayfunction as a penetration enhancer.

Exemplary penetration enhancers include, but are not limited to, fattyacids, fatty acid esters, fatty alcohols, pyrrolidones, sulfoxides,alcohols, diols and polyols, and mixtures thereof.

Exemplary fatty acids include, but are not limited to, oleic acid,capric acid, hexanoic acid, lauric acid, linoleic acid, linolenic acid,propionic acid and vaccenic acid, and mixtures thereof.

Exemplary fatty acid esters include, but are not limited to, glycerolmonolaurate, glycerol monooleate, glycerol monolinoleate, isopropylisostearate, isopropyl palmitate, isopropyl myristate, diethylsebacate,sorbitan monopalmitate, sorbitan oleate, sorbitan dilaurate, sorbitantrioleate, propylene glycol monolaurate and sucrose monolaurate, andmixtures thereof.

Exemplary fatty alcohols include, but are not limited to, cetyl alcohol,stearyl alcohol, decanol, tridecanol, lauryl alcohol, linolenyl alcoholand oleyl alcohol, and mixtures thereof.

Exemplary pyrrolidones include, but are not limited to, N-methylpyrrolidone, 2-pyrrolidone and N-cyclohexyl-2-pyrrolidone, and mixturesthereof.

Exemplary sulfoxides include, but are not limited to, dimethyl sulfoxideand decylmethyl sulfoxide, and mixtures thereof.

Exemplary alcohols include, but are not limited to, lower (C₁-C₆)alcohols and diethylene glycol monoethyl ether, and mixtures thereof.

Exemplary diols include, but are not limited to, 1,2-hexanediol,butylene glycol, diethylene glycol, dipropylene glycol, ethylhexanediol, ethylene glycol, hexylene glycol, pentylene glycol,propylene glycol, propylene glycol monolaurate, tetraethylene glycol,triethylene glycol, tripropylene glycol, polyethylene glycol andpolypropylene glycol, and mixtures thereof.

Exemplary polyols include, but are not limited to, butanetriol, glyceroland 1,2,6-hexanetriol, and mixtures thereof.

Suitably, the penetration enhancer is present in the composition in anamount from about 0.5% to about 40% by weight, such as from about 1% toabout 20% by weight or from about 5% to about 15% by weight, based onthe total weight of the composition.

Gelling Agent

The present topical pharmaceutical compositions may further comprise agelling agent. In an embodiment, the gelling agent is a mixture of twoor more gelling agents.

Exemplary gelling agents include, but are not limited to, agar,alginate, arabinoxylan, carrageenan, carboxymethylcellulose,hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, cellulose, curdlan, gelatin, gellan, β-glucan,tragacanth gum, guar gum, gum arabic, locust bean gum, pectin, starch, acarbomer, acrylate copolymers, silica, xanthan gum, salts thereof, or acombination or mixture thereof.

Suitably, the gelling agent is present in the composition in an amountfrom about 0.1% to about 2% by weight, based on the total weight of thecomposition. In one embodiment, the gelling agent is present in thecomposition in an amount from about 0.2% to about 1% by weight, based onthe total weight of the composition.

The 3,5-Dihydroxy-4-isopropyl-trans-stilbene or pharmaceuticallyacceptable salt thereof is applied to the patient for a dermatologicaldisease or disorder in a dermatologically acceptable formulation. Theseformulations include any of the various known excipients which may beapplied topically and which will permit even spreading of the activeingredient over the affected area, rapid drying, and/or increasedpenetration. Examples of suitable formulations will include solutions,milks, creams, ointments, gels, lotions, sprays, aerosols, foam, orsuspensions.

Aqueous Solution

In one embodiment, the dermatologically acceptable formulation is anaqueous solution. In this embodiment, the pharmaceutical compositioncomprises water in an amount from about 50% to about 99.9% by weight, orfrom about 70% to about 99.9% by weight. Suitably, the pH of thecomposition is adjusted to a pH of between about 2 to about 6, butpreferably to about 4 to about 6, such as about 4.5 to about 5.5. Thetopical aqueous solution may also comprise one or more of a co-solvent,a humectant, a chelating agent, an antioxidant, a preservative, afragrance, a colorant or a penetration enhancer as described herein.

Aqueous Gel

In one embodiment, the dermatologically acceptable formulation is anaqueous gel. In this embodiment, the pharmaceutical compositioncomprises water in an amount from about 50% to about 99% by weight, suchas from about 70% to about 99% by weight. Suitably, the pH of thecomposition is adjusted to a pH of between about 2 to about 6, but moreparticularly to about 4 to about 6, or about 4.5 to about 5.5.Furthermore, in this embodiment, the pharmaceutical composition willalso comprise a suitable gelling agent. The composition may furthercomprise a co-solvent, a humectant, a chelating agent, an antioxidant, apreservative, a fragrance, a colorant or a penetration enhancer, or acombination or mixture thereof

Hydroalcoholic Gel

In one embodiment the dermatologically acceptable formulation is ahydroalcoholic gel. The hydroalcoholic solution of the invention may bethickened with a gelling agent to form a hydroalcoholic gel.

In one embodiment, the hydroalcoholic gel comprises water, a loweralcohol and a suitable gelling agent. The composition may furthercomprise one or more of a co-solvent, a pH adjusting agent, a humectant,a chelating agent, an antioxidant, a preservative, a fragrance, acolorant or a penetration enhancer.

Anhydrous Solution

In one embodiment the dermatologically acceptable formulation is ananhydrous solution, that is, a solution that is substantially free orfree of water. In one embodiment, the anhydrous solution is free ofwater. In another embodiment, the anhydrous solution is substantiallyfree of water.

In one embodiment, the anhydrous solution comprises an anhydrousvehicle. In an embodiment, the anhydrous vehicle comprises one or moresolvents selected from the group consisting of a lower (C₁-C₆) alcohol,a diol and a polyol.

Suitably, the lower alcohol is selected from the group consisting ofethanol, propanol, isopropanol, n-butyl alcohol and t-butyl alcohol, andmixtures thereof. In one embodiment, the lower alcohol is ethanol. Inanother embodiment, the lower alcohol is a mixture of ethanol and one ormore other lower alcohols.

Suitably, the diol is selected from the group consisting of1,2-hexanediol, butylene glycol, diethylene glycol, dipropylene glycol,ethyl hexanediol, ethylene glycol, hexylene glycol, pentylene glycol,propylene glycol, propylene glycol monolaurate, tetraethylene glycol,triethylene glycol, tripropylene glycol and polyethylene glycol.

Suitably, the polyol is selected from the group consisting ofbutanetriol, glycerol and 1,2,6-hexanetriol.

In one embodiment, the anhydrous vehicle comprises a mixture of ethanoland propylene glycol. In another embodiment, the anhydrous vehiclecomprises a mixture of ethanol, propylene glycol and polyethyleneglycol. In yet another embodiment, the anhydrous vehicle is ethanol.

Suitably, the anhydrous vehicle is present in the composition in anamount from about 50% to about 99.5% by weight.

Anhydrous Gel

In one embodiment the dermatologically acceptable formulation is ananhydrous solution. The anhydrous solution may be thickened with agelling agent to form an anhydrous gel. In one embodiment, the anhydrousgel comprises an anhydrous vehicle and a gelling agent. The anhydrousgel may further comprise a co-solvent, a humectant, a chelating agent,an antioxidant, a preservative, a fragrance, a colorant or a penetrationenhancer, or a combination or mixture thereof.

Oleaginous Solution

In one embodiment the dermatologically acceptable formulation isformulated as oleaginous solutions. The oleaginous solutions comprise anoil and/or fat as described herein.

In one embodiment, the oil and/or fat is present in an amount from about70% to about 99.9% by weight. In another embodiment, the oil and/or fatis present in an amount from about 80% to about 99% by weight.

The oleaginous solution may further comprise a co-solvent, a humectant,a chelating agent, an antioxidant, a preservative, a fragrance, acolorant or a penetration enhancer, or a combination or mixture thereof.

Oleaginous Gel

In yet a further embodiment, the oleaginous solutions are thickened witha gelling agent to form oleaginous gels.

In one embodiment, the oleaginous gel comprises an oil and/or fat and agelling agent. Suitably, the oil and/or fat is present in an amount fromabout 70% to about 99.9% by weight, such as about 80% to about 99% byweight. The oleaginous gel may further comprise a cosolvent, ahumectant, a chelating agent, an antioxidant, a preservative, afragrance, a colorant or a penetration enhancer, or a combination ormixture thereof

Cream

In one embodiment, the dermatologically acceptable formulation is acream. In one embodiment, the cream is an oil-in-water cream. Suitably,the oil-in-water cream comprises an oil phase, a water phase, asurfactant and an antioxidant.

In one embodiment, the pH of the composition is adjusted to a pH ofbetween about 2 to about 6, such as about 4 to about 6. In anotherembodiment, the pH of the composition is adjusted to a pH of betweenabout 4.5 to about 5.5.

The composition may further comprise a co-solvent, a humectant, achelating agent, a preservative, a fragrance, a colorant or apenetration enhancer, or a combination or mixture thereof.

In one embodiment, the present invention provides a topicalpharmaceutical emulsion composition comprising3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase comprising an oil and/or fat in anamount from about 5% to about 45% by weight, a water phase comprisingwater in an amount from about 25% to about 85% by weight, a surfactantin an amount from about 1% to about 20% by weight, and an antioxidant inan amount from about 0.001% to about 5% by weight, wherein the emulsioncomposition is homogenous, and wherein all percentages are based on thepercent by weight of the final composition, and all totals equal 100% byweight.

In one embodiment, the 3,5-Dihydroxy-4-isopropyl-trans-stilbene orpharmaceutically acceptable salt thereof is solubilized in the oil phaseof the emulsion composition. In another embodiment, if the oil phasecontains mineral oil or petrolatum, then a second oil phase component ispresent, and if the oil phase contains both mineral oil and petrolatumthen a third oil phase component is present. In one embodiment, the oilphase is substantially free from petrolatum. In another embodiment, theoil phase contains ≤3%, or ≤2%, or ≤1% petrolatum. In anotherembodiment, if the oil phase contains both mineral oil and petrolatumthen at least a third oil phase component is present which is an esterand/or an ester of glycerin, suitably an ester of glycerin, such as amedium chain triglyceride.

In one embodiment, the present invention provides a topicalpharmaceutical emulsion composition comprising3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase comprising an oil and/or fat in anamount from about 5% to about 35% by weight, a water phase comprisingwater in an amount from about 25% to about 85% by weight, a surfactantin an amount from about 1% to about 20% by weight, and an antioxidant inan amount from amount from about 0.001% to about 5% by weight, whereinthe emulsion composition is homogenous and the3,5-Dihydroxy-4-isopropyl-trans-stilbene or pharmaceutically acceptablesalt thereof is solubilized in the oil phase of the emulsioncomposition, and wherein all percentages are based on the percent byweight of the final composition, and all totals equal 100% by weight.

In another embodiment, the present invention provides a topicalpharmaceutical emulsion composition comprising3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase comprising an oil and/or fat in anamount from about 5% to about 35% by weight, a water phase comprisingwater in an amount from about 30% to about 80% by weight, a surfactantin an amount from about 5% to about 15% by weight, and an antioxidant inan from amount from about 0.001% to about 5% by weight, wherein theemulsion composition is homogenous, and wherein all percentages arebased on the percent by weight of the final composition, and all totalsequal 100% by weight. In another embodiment the3,5-Dihydroxy-4-isopropyl-trans-stilbene or pharmaceutically acceptablesalt thereof is solubilized in the oil phase of the emulsioncomposition.

In one embodiment, the composition may further comprise one or moreco-solvents in the composition present in an amount from about 1% toabout 30% by weight, based on the total weight of the composition. Inanother embodiment, the composition may comprise a preservative presentin an amount from about 0.01% to about 2% by weight, based on the totalweight of the composition. In another embodiment, the composition mayfurther comprise a chelating agent present in an amount from about 0.01%to about 1% by weight, based on the total weight of the composition. Inanother embodiment, the composition may further comprise a pH adjustingagent present in an amount from about 0.01% to about 10% by weight,based on the total weight of the composition. In another embodiment, theoil phase comprises an ester and/or an ester of glycerin, suitably anester of glycerin which is a medium chain triglycerides (MCT) present inan amount from about 2% to about 30% by weight, based on the totalweight of the composition.

In another embodiment the present invention provides a topicalpharmaceutical emulsion composition comprising3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase comprising an oil and/or fat in anamount from about 5% to about 35% by weight, a water phase comprisingwater in an amount from about 30% to about 80% by weight, a surfactantin an amount from about 5% to about 15% by weight, an antioxidant in anamount from amount from about 0.001% to about 5% by weight, a pHadjusting agent in an amount from about 0.01% to about 10% by weight,wherein the emulsion composition is homogenous, and wherein allpercentages are based on the percent by weight of the final composition,and all totals equal 100% by weight. In another embodiment, the water ispresent in an amount from about 55% to about 75% by weight, based on thetotal weight of the composition. In another embodiment, the oil and/orfat is present in an amount from about 5% to about 25% by weight, basedon the total weight of the composition. In another embodiment, the oiland/or fat is present in an amount from about 5% to about 15% by weight,based on the total weight of the composition. In one embodiment, the3,5-Dihydroxy-4-isopropyl-trans-stilbene or pharmaceutically acceptablesalt thereof is solubilized in the oil phase of the emulsioncomposition. In one embodiment, the composition may further comprise oneor more co-solvents in the composition present in an amount from about1% to about 30% by weight, based on the total weight of the composition.

The present invention also provides for a pharmaceutical productcomprising a combination of therapeutic agents, for simultaneous,separate or sequential use in the treatment of conditions for whichadministration of 3,5-Dihydroxy-4-isopropyl-trans-stilbene or apharmaceutically acceptable salt thereof is indicated.

In the context of this specification, the term “simultaneously” whenreferring to simultaneous administration of the relevant drugs means atexactly the same time, as would be the case, for example in embodimentswhere the drugs are combined in a single preparation. In otherembodiments, “simultaneously” can mean one drug is administered a shortduration after another, wherein “a short duration” means a durationwhich allows the drugs to have their intended synergistic effect.

In light of the foregoing, the present invention also relates tocombination therapy, which may be a comprised of a simultaneous orco-administration, or serial administration of a combination ofcompounds or pharmaceutical compositions of the present invention withother active drug or therapeutic agents, and where such administrationalso is determined by one of ordinary skill in the art.

In such an aforementioned combination composition, the dosage form ofthe present invention, each of the active drug components are containedin effective dosage amounts.

In another aspect, the present invention relates to a combinationtherapy, where the second therapeutic agent may be administered before,concurrent with or after administration of the3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof whether in the same formulation or in a separateformulation and whether or not the second therapeutic agent isadministered by the same topical route, e.g. it may be given orally,intravenously intramuscularly, opthalmically, vaginally, rectally, etc.

In other words, the 3,5-Dihydroxy-4-isopropyl-trans-stilbene or apharmaceutically acceptable salt thereof may be administered together,contemporaneously or sequentially in either order to the site ofadministration, or to a desired site of action. The order ofadministration is not deemed necessary, provided that if topicallyadministered they are in contact at some point together at the site ofadministration or desired site of action. If both are present in thesame vehicle they provide ease of administration to the patient, andperhaps increased compliance, but it is not required for the inventionherein.

In another embodiment, the topical pharmaceutical compositions havegreater than 90% of the original concentration of3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof remaining after storage of the composition for 3months at 40° C.

In one embodiment, the present invention provides a topicalpharmaceutical emulsion composition comprising 3,5-Dihydroxy-4sopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof,an oil phase, a water phase, a surfactant, and an antioxidant, andwherein the emulsion is homogenous. In another embodiment the3,5-Dihydroxy-4-isopropyl-trans-stilbene or pharmaceutically acceptablesalt thereof is solubilized in the oil phase of the emulsioncomposition. In another embodiment, the composition is an oil-in-watercream.

In one embodiment, the present invention provides a topicalpharmaceutical emulsion composition comprising 3,5-Dihydroxy-4sopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof,an oil phase, a water phase, a surfactant, an antioxidant and apreservative, and wherein the emulsion composition is homogenous. Inanother embodiment the 3,5-Dihydroxy-4-isopropyl-trans-stilbene orpharmaceutically acceptable salt thereof is solubilized in the oil phaseof the emulsion composition. In another embodiment, the composition isan oil-in-water cream.

In one embodiment, the present invention provides a topicalpharmaceutical emulsion composition comprising3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant, anantioxidant, a preservative and a co-solvent, and wherein the emulsioncomposition is homogenous. In another embodiment the3,5-Dihydroxy-4-isopropyl-trans-stilbene or pharmaceutically acceptablesalt thereof is solubilized in the oil phase of the emulsioncomposition. In another embodiment, the composition is an oil-in-watercream.

In one embodiment, the present invention provides a topicalpharmaceutical emulsion composition comprising3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant, anantioxidant, a preservative, a co-solvent and a pH adjusting agent, andwherein the emulsion is homogenous. In another embodiment, the3,5-Dihydroxy-4-isopropyl-trans-stilbene or pharmaceutically acceptablesalt thereof is solubilized in the oil phase of the emulsioncomposition. In another embodiment, the composition is an oil-in-watercream.

In another embodiment, the present invention provides a topicalpharmaceutical emulsion composition comprising:

-   -   i) 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a        pharmaceutically acceptable salt thereof;    -   ii) an oil phase comprising an oil and/or fat;    -   iii) a water phase, comprising water;    -   iv) a surfactant;    -   v) an antioxidant;    -   vi) a pH adjusting agent;    -   vii) a chelating agent;    -   viii) a preservative; and    -   ix) a co-solvent, and wherein the emulsion is homogenous.

Suitably, the 3,5-Dihydroxy-4-isopropyl-trans-stilbene or apharmaceutically acceptable salt thereof is solubilized in the oil phaseof the emulsion composition, and suitably the composition is anoil-in-water cream.

In one embodiment, if the oil phase contains mineral oil or petrolatum,then a second oil phase component is present, and if the oil phasecontains both mineral oil and petrolatum than a third oil phasecomponent is also present. In one embodiment, the oil phase issubstantially free from petrolatum. In another embodiment the oil phasecontains ≤3%, or ≤2%, or ≤1% petrolatum. In another embodiment, if theoil phase contains both mineral oil and petrolatum than at least a thirdoil phase component is present which is an ester and/or an ester ofglycerin, suitably a an ester of glycerin such as as medium chaintriglyceride. In another embodiment, if the oil phase comprises mineraloil then a second oil phase component is present which is an esterand/or an ester of glycerin, suitably an ester of glycerin, such as amedium chain triglyceride.

In another embodiment, the present invention provides a topicalpharmaceutical emulsion composition comprising:

-   3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically    acceptable salt thereof,-   an oil phase comprising an oil and/or fat,-   a water phase comprising water,-   a surfactant comprising an ethoxylated fatty alcohol ether; and    wherein the emulsion is homogenous.

In another embodiment, the present invention provides a topicalpharmaceutical emulsion composition comprising:

-   3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically    acceptable salt thereof,-   an oil phase comprising an oil and/or fat,-   a water phase comprising water,-   a surfactant comprising an ethoxylated fatty alcohol ether,-   an antioxidant selected from the group consisting of butylated    hydroxytoluene, propyl gallate and tocopherol, and mixtures thereof;    and wherein the emulsion is homogenous.

In another embodiment, the present invention provides a topicalpharmaceutical emulsion composition comprising:

-   3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically    acceptable salt thereof,-   an oil phase comprising an oil and/or fat,-   a water phase comprising water,-   a surfactant comprising an ethoxylated fatty alcohol ether,-   an antioxidant selected from the group consisting of butylated    hydroxytoluene, propyl gallate and tocopherol, and mixtures thereof,-   a chelating agent, and wherein the emulsion is homogenous.

In another embodiment, the present invention provides a topicalpharmaceutical emulsion composition comprising:

-   -   i) 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a        pharmaceutically acceptable salt thereof,    -   ii) an oil phase comprising an oil and/or fat,    -   a water phase comprising water,    -   a surfactant comprising an ethoxylated fatty alcohol ether,    -   an antioxidant selected from the group consisting of butylated        hydroxytoluene, propyl    -   gallate and tocopherol, and mixtures thereof,    -   a chelating agent,    -   a preservative selected from the group consisting of benzyl        alcohol, phenoxyethanol and benzoic acid, and mixtures thereof,        and wherein the emulsion is homogenous.

In another embodiment, the present invention provides a topicalpharmaceutical emulsion composition comprising:

-   -   3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically        acceptable salt thereof,    -   an oil phase comprising an oil and/or fat,    -   a water phase comprising water,    -   a surfactant comprising an ethoxylated fatty alcohol ether,    -   an antioxidant selected from the group consisting of butylated        hydroxytoluene, propyl    -   gallate and tocopherol, and mixtures thereof,    -   a chelating agent,    -   a preservative selected from the group consisting of benzyl        alcohol, phenoxyethanol and benzoic acid, and mixtures thereof,    -   a co-solvent, and    -   a pH adjusting agent, and wherein the emulsion is homogenous.

Suitably, the 3,5-Dihydroxy-4-isopropyl-trans-stilbene orpharmaceutically acceptable salt thereof is solubilized in the oil phaseof the emulsion composition. Suitably, the composition is anoil-in-water cream. In one embodiment, if the oil phase comprisesmineral oil or petrolatum, then a second oil phase component is present,and if the oil phase contains both mineral oil and petrolatum then athird oil phase component is present. In one embodiment, the oil phaseis substantially free from petrolatum. In another embodiment, the oilphase contains ≤3%, or ≤2%, or ≤1% petrolatum. In another embodiment, ifthe oil phase contains both mineral oil and petrolatum at least a thirdoil phase component is present which is an ester and/or an ester ofglycerin, suitably an ester of glycerin such as a medium chaintriglyceride. In another embodiment, if the oil phase contains mineraloil then a second oil phase component is present which is an esterand/or an ester of glycerin, suitably an ester of glycerin such as amedium chain triglyceride.

In another embodiment, the present invention provides a topicalpharmaceutical emulsion composition comprising:

-   -   3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically        acceptable salt thereof,    -   an oil phase comprising an oil and/or fat which is medium        chained triglycerides,    -   a water phase comprising water,    -   a surfactant comprising an ethoxylated fatty alcohol ether,    -   an antioxidant which is butylated hydroxytoluene,    -   a chelating agent which is EDTA or a salt thereof,    -   a preservative which is benzoic acid,    -   a co-solvent comprising a mixture of propylene glycol and        diethylene glycol monoethyl    -   ether, and    -   a pH adjusting agent which is a citrate/citric acid buffer,    -   wherein the pH of the composition is adjusted to a pH of from        about 4.5 to about 6.5, and    -   wherein the emulsion is homogenous.

Suitably, the 3,5-Dihydroxy-4-isopropyl-trans-stilbene orpharmaceutically acceptable salt thereof is solubilized in the oil phaseof the emulsion composition. Suitably, the composition is anoil-in-water cream.

In all of the compositions described herein, the amount of3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof which may be present in a composition may rangefrom about 0.25% to about 2% by weight of composition. In oneembodiment, the amount may be 0.25%, 0.3%, 0.4%, 0.5%, 0.75%, 1.0%,1.25%, 1.5%, 1.75% or 2.0% by weight, based on the total weight of thecomposition. In another embodiment, the amount is about 0.25% to about0.50% by weight, based on the total weight of the composition. Inanother embodiment, the amount is about 0.25% by weight, based on thetotal weight of the composition. In another embodiment, the amount isabout 0.50% by weight, based on the total weight of the composition. Inanother embodiment, the amount is about 0.75% by weight, based on thetotal weight of the composition. In another embodiment, the amount isabout 1.0% by weight, based on the total weight of the composition.

In yet another embodiment of the invention there is a topicalpharmaceutical emulsion composition comprising (a) an oil phase; (b) anaqueous/water phase; (c) at least one cosolvents; (d) at least onesurfactant; (e) an antioxidant, and (f) the active ingredient3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof. In one embodiment the oil phase containsmineral oil. In another the oil phase contains petrolatum. In anotherembodiment, the oil phase contains both mineral oil and petrolatum. Inanother embodiment the oil phase contains mineral oil and/or petrolatumeach independently present in amounts greater than 3% w/w. In anotherembodiment the oil phase contains mineral oil and/or petrolatum eachindependently present in amounts greater than 5% w/w. In anotherembodiment the oil phase contains mineral oil and/or petrolatum eachindependently present in amounts greater than 10% w/w. In anotherembodiment the oil phase contains mineral oil and/or petrolatum eachindependently present in amounts greater than 15% w/w. In anotherembodiment the oil phase contains mineral oil and/or petrolatum presentin amounts greater than 5% w/w in any combination. In another embodimentthe oil phase contains mineral oil and/or petrolatum present in amountsgreater than 10% w/w in any combination. In another embodiment the oilphase contains mineral oil and/or petrolatum present in amounts greaterthan 15% w/w in any combination. In another embodiment the oil phasecontains mineral oil and/or petrolatum present in amounts greater than20% w/w in any combination. In another embodiment the oil phase containsmineral oil and/or petrolatum present in amounts greater than 25% w/w inany combination.

While not wishing to be limited to this explanation it is believed thatwhen the oil phase contains components that the active ingredient is notsoluble in, such as mineral oil and/or petrolatum as exemplified hereinby Formulations 1, 12 and 41-42 the active ingredient is solubilized inthe co-solvents, such as but not limited to propylene glycol and/ordiethylene glycol monoethyl ether. Subsequently, when the aqueous phaseis added to the oil phase, the active ingredient might be soluble inboth the aqueous and/or the oil phase depending on where and how much ofthe co-solvent(s) partition into the system.

In another embodiment, the present invention provides a topicalpharmaceutical emulsion composition comprising:

-   -   i) 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a        pharmaceutically acceptable salt thereof;    -   ii) an oil phase comprising at least one oil and/or fat which is        mineral oil or petrolatum;    -   iii) an aqueous phase comprising water;    -   iv) at least one co-solvent; and    -   v) a surfactant, and optionally, in this embodiment, the        pharmaceutical composition may also comprise a suitable gelling        agent, a humectant, a pH adjusting agent, a chelating agent, a        preservative, a fragrance, a colorant or a penetration enhancer,        or a combination or mixture thereof; and wherein all percentages        are based on the percent by weight of the final composition, and        all totals equal 100% by weight.

Suitably the composition is an oil-in-water cream. In one embodiment thesurfactant comprises an ethoxylated fatty alcohol ether. In anotherembodiment, the co-solvent comprises a mixture of propylene glycol anddiethylene glycol monoethyl ether.

In another embodiment, the present invention provides a topicalpharmaceutical emulsion composition comprising:

-   -   i) 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a        pharmaceutically acceptable salt thereof;    -   ii) an oil phase comprising at least one oil and/or fat which is        mineral oil or petrolatum in an amount from about 5% to about        45% by weight,    -   iii) an aqueous phase comprising water in an amount from about        50% to about 99.9% by weight,    -   iv) at least one co-solvent in an amount from about 1% to about        30% by weight;    -   v) a surfactant in an amount from about 1% to about 20% by        weight;    -   vi) an antioxidant in an amount from amount from about 0.001% to        about 5% by weight, and optionally, a gelling agent, a        humectant, a pH adjusting agent, a chelating agent, a        preservative, a fragrance, a colorant or a penetration enhancer,        or a combination or mixture thereof; and wherein all percentages        are based on the percent by weight of the final composition, and        all totals equal 100% by weight

In one embodiment the surfactant comprises an ethoxylated fatty alcoholether. In another embodiment, the co-solvent comprises a mixture ofpropylene glycol and diethylene glycol monoethyl ether.

In another embodiment, the antioxidant is selected from the groupconsisting of butylated hydroxytoluene, propyl gallate and tocopherol,and mixtures thereof.

In another embodiment, the co-solvent comprises a mixture of propyleneglycol and diethylene glycol monoethyl ether.

In another embodiment, the present invention provides a topicalpharmaceutical emulsion composition comprising:

-   -   i) 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a        pharmaceutically acceptable salt thereof;    -   ii) an oil phase comprising at least one oil and/or fat which is        mineral oil or petrolatum;    -   iii) an aqueous phase comprising water;    -   iv) at least one co-solvent;    -   v) a surfactant;    -   vi) an antioxidant; and    -   vii) a chelating agent, and optionally, a gelling agent, a        humectant, a pH adjusting agent, a preservative, a fragrance, a        colorant or a penetration enhancer, or a combination or mixture        thereof; and wherein all percentages are based on the percent by        weight of the final composition, and all totals equal 100% by        weight.

In another embodiment, the co-solvent comprises a mixture of propyleneglycol and diethylene glycol monoethyl ether.

In one embodiment the surfactant comprises an ethoxylated fatty alcoholether.

In another embodiment, the antioxidant is selected from the groupconsisting of butylated hydroxytoluene, propyl gallate and tocopherol,and mixtures thereof.

In another embodiment, the composition may further comprise a chelatingagent present in an amount from about 0.01% to about 1% by weight, basedon the total weight of the composition. In an embodiment, the chelatingagent is a mixture of two or more chelating agents.

In another embodiment, the present invention provides a topicalpharmaceutical emulsion composition comprising:

-   -   i) 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a        pharmaceutically acceptable salt thereof;    -   ii) an oil phase comprising at least one oil and/or fat which is        mineral oil or petrolatum;    -   iii) an aqueous phase comprising water;    -   iv) at least one co-solvent;    -   v) a surfactant;    -   vi) an antioxidant,    -   vii) a chelating agent, and    -   viii) a preservative, and optionally, a gelling agent, a        humectant, a pH adjusting agent, a preservative, a fragrance, a        colorant or a penetration enhancer, or a combination or mixture        thereof; and wherein all percentages are based on the percent by        weight of the final composition, and all totals equal 100% by        weight.

In one embodiment the surfactant comprises an ethoxylated fatty alcoholether. In another embodiment, there are 2 surfactants present in theformulation. Suitably, when there are 2 surfactants present, eachsurfactant is present in an amount from about 0.5% to about 5% byweight, based on the total weight of the composition. In anotherembodiment, there are 3 surfactants present in the formulation.Suitably, when there are 3 surfactants present, each surfactant ispresent in an amount from about 0.5% to about 5% by weight, based on thetotal weight of the composition. Similarly, if there are 4 or moresurfactants present they are each present in an amount from about 0.5%to about 5% by weight, based on the total weight of the composition.

In another embodiment, the antioxidant is selected from the groupconsisting of butylated hydroxytoluene, propyl gallate and tocopherol,and mixtures thereof.

In another embodiment, the co-solvent comprises a mixture of propyleneglycol and diethylene glycol monoethyl ether.

In one embodiment the chelating agent is EDTA or a salt thereof.

In another embodiment the preservative is benzoic acid.

In another embodiment, the present invention provides a topicalpharmaceutical emulsion composition comprising:

-   -   i) 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a        pharmaceutically acceptable salt thereof,    -   ii) an oil phase comprising at least one oil and/or fat which is        mineral oil or petrolatum,    -   iii) a water phase comprising water,    -   iv) a surfactant comprising an ethoxylated fatty alcohol ether,    -   v) an antioxidant,    -   vi) a chelating agent,    -   vii) a preservative,    -   viii) a co-solvent, and    -   ix) a pH adjusting agent, and optionally, a gelling agent, a        humectant, a preservative, a fragrance, a colorant or a        penetration enhancer, or a combination or mixture thereof; and        wherein all percentages are based on the percent by weight of        the final composition, and all totals equal 100% by weight.

In one embodiment the surfactant comprises an ethoxylated fatty alcoholether.

In another embodiment, the antioxidant is selected from the groupconsisting of butylated hydroxytoluene, propyl gallate and tocopherol,and mixtures thereof.

In another embodiment the preservative selected from the groupconsisting of benzyl alcohol, phenoxyethanol and benzoic acid, andmixtures thereof,

In another embodiment, the co-solvent comprises a mixture of propyleneglycol and diethylene glycol monoethyl ether.

In one embodiment the chelating agent is EDTA or a salt thereof.

In another embodiment the preservative is benzoic acid,

In another embodiment, the pH adjusting agent is a citrate/citric acidbuffer.

Alternatively when discussed in a biological function, the term applieddose may be used. As used herein, applied dose is defined as the amountof drug product applied per body surface area, denoted in mg/cm² units.The amount of active ingredient delivered to the skin layers (epidermisor dermis) may be denoted in nanograms (ng) or micrograms (μg) per skinsection or per cm². Alternatively, the amount of active ingredientdelivered to epidermis or dermis may be denoted as % of the applieddose. The amount of active ingredient delivered to the receiving fluidmay be denoted as cumulative amount in ng or ng/cm².

In an embodiment, the emulsion composition comprises3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof in a composition that has a human skinpenetration measured in vitro of at least 0.01-10% of the applied doseof the active ingredient into the epidermis over a period of about 1 toabout 72 hours. In another embodiment, the time period is from about 2to about 24 hours. In another embodiment, the time period is about 1 toabout 15 hours. The % of applied dose of the active ingredient may befrom 0.01-10%, 0.01-5%, 0.01-3%, 0.4-2.3% w/w.

In one embodiment, the emulsion composition comprises the3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof in a composition that has human skin penetrationmeasured in vitro of at least 0.01-10% of the applied dose of the activeingredient into the dermis over a period of about 1 to about 72 hours.In another embodiment, the time period is from about 2 to about 24hours. In another embodiment, the time period is about 6 to about 15hours. The % of applied dose of the active ingredient may be from0.01-7.5%, 0.01-5%, 0.01-3%, 0.3-1.7%. In an alternative embodiment, theapplied dose measured in an amount of 1-2 μg/cm², e.g. 0.5% w/v.

As illustrated in FIG. 3, Formulation 17 delivers a higher relativeamount of the active ingredient into the dermis compared withFormulations 1 and 12. Conversely, Formulation 17 deliveredcomparatively less into the receiving fluid, as illustrated in FIG. 4.Formulations 1 and 12 were very comparable, with minor changes in buffercomposition and preservative (Tables 1 and 4, respectively). The invitro human skin flux and dermal deposition results confirmed suchsimilarities and enabled the extrapolation of further data comparison ofany other formulation with Formulation 12 and, therefore withFormulation 1.

Although the two formulations shown in FIGS. 5 and 6 have differingamounts of active ingredient (Formulation 12 is 0.5% and Formulation 21is 1%), the same conclusions can be reached when normalization isapplied, e.g. Formulation 21 also shows a higher relative amount in thedermis as compared to the receiving fluid, which is measured as skinflux values and cumulative amounts, as normalized for applied dose. Thecumulative amount represents how much active ingredient penetratesthrough the skin (500±100 μm), reaching the receiving fluid, over aspecific period of time. The skin flux represents the slope of thecumulative amount curve, characterized as a linear phase and alsoreferred as steady state (R²≥0.99), observed during the course of theexperiment.

By converting the dermis amount from each time point (FIG. 5) from % ofapplied dose to ng of the active ingredient and dividing this value bythe respective cumulative amount in ng (FIG. 6) at 3, 6, 9, 12 and 15hours, it was demonstrated that Formulation 21 promoted a targeteddelivery to the dermis, resulting in less active ingredient penetratingthe receiving fluid (unbound active ingredient penetrating deeper than500±100 μm). The ratios dermis/cumulative amount in the receiving fluid(ng/ng) for Formulation 21 ranged from 9038.0 and 12937 at 3 hours and 6hours, respectively, to 909.3 and 1044.0 at 12 hours and 15 hours,respectively. Formulation 12 showed a significantly different profile,with its ratios ranging from 7870.2 and 1428.7 at 3 hours and 6 hours,respectively, to 215.7 and 233.93 at 12 hours and 15 hours,respectively. Since Formulation 21 showed good dose proportionality atdifferent active ingredient strengths ranging from 0.5% (Formulation 17)to 2.0% (Formulation 22) as observed in FIGS. 3 and 4, the ratio ofdermis/cumulative amount explained above is valid to demonstrate thesuperiority of Formulation 21 over 12, despite their different strength(1.0% and 0.5%, respectively).

The lag phase for the active ingredient in the formulations ranged from8 to 12 hours post-dosing—after this period of time the activeingredient reached its steady state and demonstrated a constant skinflux. The ratio dermis (ng)/skin flux (ng*cm²/hr) was used as anadditional parameter to characterize the targeted delivery to the dermisobserved for Formulation 21 in comparison to Formulation 12. From datashown on FIG. 6 the derived skin flux (slope with a R²≥0.99) forFormulations 21 and 12 are, respectively, 0.7251 ng*cm²/hr and 0.9935ng*cm²/hr. Considering the different strengths of Formulations 21 and 12(1.0% and 0.5%, respectively), the normalized skin flux values (skinflux divided by active ingredient strength) were 0.7251 ng*cm²/hr and1.987 ng*cm²/hr, respectively. Using these normalized skin flux valuesand the dermis amounts converted to ng (from FIG. 6) covering the steadystate region (after 8 hours), the ratios dermis (ng)/normalized skinflux (ng*cm²/hr) were calculated. Formulation 21 demonstrated aselective delivery of the active ingredient to the dermis, with ratiosof 1599.5, 1132.6 and 3200.7 at 9 hours, 12 hours and 15 hours,respectively. Formulation 12 showed a significantly different deliveryprofile, with ratios of 213.25, 108.57 and 117.73 at 9 hours, 12 hoursand 15 hours, respectively.

One embodiment of the invention is a topical pharmaceutical emulsioncomposition comprising a therapeutically effective amount of3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant andan antioxidant, wherein the emulsion is homogenous, and wherein thecomposition administered in an in vitro system results in a ratio ofdermis amounts (ng) measured at steady state to normalized (by activestrength) skin flux (ng*cm²/hr) from 1000 to 5000, using freshly excisedabdominal human skin. In one embodiment, the3,5-Dihydroxy-4-isopropyl-trans-stilbene or pharmaceutically acceptablesalt thereof is solubilized in the oil phase of the emulsioncomposition.

In another embodiment of the invention there is a homogenous topicalpharmaceutical emulsion composition comprising an effective amount of3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant andan antioxidant, wherein the composition produces an area under the curve(AUC) AUC(0-tau) of less than 30 ng*h/mL, or less than 23.5 ng*h/mL orless than 16 ng*h/mL in a human upon administration to the skin in anamount not exceeding 35% Body Surface Area (BSA). In another embodiment,the amount is not exceeding 30% BSA.

In one embodiment, the AUC is at steady state. In another embodiment,the amount of body surface area (BSA) for which the drug is applied tois less than 50%, in another embodiment the amount is less than 35%, inanother embodiment the amount is less than 30%. It is recognized that ifthe BSA is >10% than the AUC may be increased accordingly.

As used herein, the term “AUC(0-last) means the area under the plasmaconcentration versus time curve, from time 0 to the last measurableconcentration as calculated by the log-linear trapezoidal method.

As used herein, the term “AUC(0-12)” means the area under the plasmaconcentration versus time curve, from time 0 to the 12-hour time point,as calculated by the log-linear trapezoidal method.

As used herein, the term “AUC(0-tau)” means the area under the plasmaconcentration versus time curve from time 0 to end of the dosinginterval, as calculated by the log-linear trapezoidal method.

In another embodiment of the invention there is a homogenous topicalpharmaceutical emulsion composition comprising an effective amount of3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant andan antioxidant, wherein the composition produces a C_(max) (maximumplasma level of drug) at steady state, and the amount of body surfacearea (BSA) for which the active ingredient (1% strength) is applied tois 15-35% and produces a C_(max) below 4 ng/ml and an AUC (0-8h) of nomore than 16 ng·h/mL.

Study Formulation Formulation 1a Formulation 21 Age 18-65 y 18-65 yDisease duration ≥6 months diagnosis of AD ≥6 months diagnosis of ADAffected area 1-10% BSA, excluding face, 15-35% BSA, excluding scalpgroin, scalp, genitals IGA (0-5) 2-3 (mild-moderate) ≥3(moderate-severe) Average % BSA treated 2.7% (1-7%) 19.8% (15-33%) Studyduration 28 day 21 day Study treatment Vehicle, 0.5%, 1% BID 1%, 2% BID(no vehicle control) Subject numbers N = 12/10/12 (completed) N = 6/2(completed) PK sampling scheme Pre-dose, 1, 2, 4, 6, 8 h post- Pre-dose,1, 2, 4, 8, 10, 12, 24 h dose post-dose LLOQ 0.1 ng/mL = 100 pg/mL 40pg/mL

1% BID cohort data only N 12 6 Day 1 Cmax (ng/mL) 0.46 (0-3.32) 1.23(0.2-3.96) Day 1 AUC(0-8) 1.22 (0-8.61) 5.56 (1.05-15.14) (ng · h/mL)IGA score change from 42% (0%-100%) 55% (33%-75%) baseline at Day 21 BSAaffected change from 52% (−21%-100%) 77% (56%-94%) baseline at Day 21

Atopic Dermatitis is evaluated clinically and is based on historicalfeatures, morphology, distribution of skin lesions and associatedclinical signs. Many formal sets of criteria have been developed to aidin classification. For measurement of disease severity, at least 28different scales exist. Most commonly used include SCORAD index, theEczema Area and Severity Index (EASI), the Investigators GlobalAssessment (IGA) and the Six area, Six sign Atopic Dermatitis (SASSAD)severity score. For purposes herein, the IGA scale or EASI scale will bereferenced.

IGA is a static 5-point morphological assessment of overall diseaseseverity, as determined by the physician, using the clinicalcharacteristics of erythema, infiltration, papulation, oozing, andcrusting as guidelines. The IGA is made without reference to theprevious IGA scores.

IGA allows investigators to assess overall disease severity at one giventime point, and it consists of a 6-point severity scale from clear tovery severe disease (0=clear, 1=almost clear, 2=mild disease, 3=moderatedisease, 4=severe disease; in some instances a score of 5=very severedisease may be used, although rarely). IGA uses clinical characteristicsof erythema, infiltration, papulation, oozing and crusting as guidelinesfor the overall severity assessment. While it appears that IGA has notbeen validated as an outcome measure, IGA has been used to validateother outcome scales as one “gold standard.” While the combined use ofIGA with another validated scale does not make IGA itself a stand-alone,validated instrument, IGA appears to correlate well with the EASI and isconsidered an instrument with reasonable face validity.

The EASI scoring system is a clinical tool for assessing the severity ofAD that takes into account the overall severity of erythema,infiltration/papulation, excoriation, and lichenification, as well asthe extent of BSA affected with AD. The 4 clinical signs are each gradedon a 4 point scale (0 to 3) for each of the 4 specified body regions(head and neck, upper extremities, lower extremities, and trunk). EASIis also a static assessment made without reference to previous scores.

One embodiment of the invention is a method of treatment of atopicdermatitis (AD) in a patient in need thereof comprising administering tosaid patient a topical pharmaceutical emulsion composition comprising aneffective amount of active 3,5-Dihydroxy-4-isopropyl-trans-stilbene or apharmaceutically acceptable salt thereof, an oil phase, a water phase, asurfactant, and an antioxidant, wherein the emulsion composition ishomogenous, and wherein the dosing is until the patient achieves a IGAscore of clear (0) or almost clear (1) is reached or the patient has a2-point improvement in the IGA score. In one embodiment, the active issolubilized in the oil phase of the composition.

In one embodiment, the patient achieves an IGA score of clear (0) oralmost clear (1) from baseline. In another embodiment, the patientachieves a 2-point improvement from baseline on the IGA score. As adegree of measurement of severity, the patient will have started with anIGA score of ≥3 at baseline for purposes herein.

In one embodiment, the time the patient maintains without relapse, e.g.post treatment is 1 month or greater; or 2 months or greater, or 3months or greater. In one embodiment, the course of treatment is 28weeks or less in duration of treatment, or is 21 weeks or less induration of treatment, or is 16 weeks or less in duration of treatment,or is 12 weeks or less, or is 8 weeks or less. In one embodiment of theinvention the time to relapse is not influenced by the duration oftreatment.

In another embodiment, there is a method of improving the % body surfacearea (BSA) of a person affected with atopic dermatitis (AD), the methodcomprising administering to said person a topical pharmaceuticalemulsion composition comprising an effective amount of3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant, andan antioxidant, wherein the emulsion composition is homogenous, andwherein the % BSA improvement seen in the patient is from about ≥10-29%,or is >≥ than 30-49% or is ≥50-69% or is ≥70-89%, or is 90-100%.

Pruritus is the most frequent symptom of AD and potentially has thegreatest effect on quality of life. In another embodiment, there is amethod of reducing pruritus in a person with atopic dermatitis (AD)comprising administering to said person a topical pharmaceuticalemulsion composition comprising an effective amount of3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant, andan antioxidant, and wherein the emulsion composition is homogenous, andthe time to reduction of pruritus, and/or the % BSA affected withpruritus is reduced from a baseline measurement. In one embodiment, theformulations of the present invention may be compared to formulation 1or 12.

One embodiment of the invention is a method of obtaining optimal dosingfor the treatment of atopic dermatitis in a patient in need thereof, themethod comprising administering to said patient a topical pharmaceuticalemulsion composition comprising an effective amount of3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant, andan antioxidant, and wherein the emulsion is homogenous, and dosingcontinues until the patient achieves a IGA score of clear or almostclear is reached or a 2 point reduction of IGA score is achieved. In oneembodiment the patient achieves a IGA score of clear or almost clear. Inone embodiment, the course of treatment is 28 weeks or less in durationof treatment, or is 21 weeks or less, or is 16 weeks or less in durationof treatment, or is 12 weeks or less in duration of treatment. In oneembodiment, the time to relapse post treatment is 3 months or greater.In another embodiment, the time to relapse post treatment is 1 month orgreater. In another embodiment, the time to relapse post treatment is 3months or greater. In another embodiment, the time to relapse posttreatment is 6 months or greater. In one embodiment of the invention thetime to relapse is not influenced by the duration of treatment.

Another embodiment of the invention is a method for reducing the time toachieving a >50% improvement in IGA scores of clear or almost clear or a2-point reduction in IGA score in a patient with atopic dermatitis inneed thereof, the method comprising administering to said patient atopical pharmaceutical emulsion composition comprising an effectiveamount of 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant, andan antioxidant, wherein the emulsion composition is homogenous. Asuitable comparator formulation would be formulation 1/la or 12 (ofsimilar % w/w active). In one embodiment, the time to achievement of the50% reduction is at 12 weeks. In another embodiment, the time toachievement of the 50% reduction is at 8 weeks.

In one embodiment, the amount of3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, administered daily is from 10 mg to 100 mg. Inanother embodiment, the daily amount administered is from 10 mg to 50mg.

In a similar manner, psoriasis can be assessed. Of the many psoriasisassessment tools currently available, the Psoriasis Area and SeverityIndex (PAST) and Physician Global Assessment (PGA) tools are most used.A PASI score is used to measure the severity and extent of psoriasis.

PASI examines four body regions: i) the head and neck, ii) the hands andarms, iii) the chest, abdomen and back (trunk) and iv) the buttocks,thighs and legs. Each region is given a score to show how much of theregion is affected by psoriasis (area) and a score to record how bad thepsoriasis is (severity). The area score can range from 0 (no psoriasis)to 6 (all of the skin affected). The severity score for each region isreached by adding scores for redness, thickness and scale, each of whichis graded from 0 to 4, giving a maximum of 12. A PASI score of >10 isgenerally used to indicate a patient with moderate to severe plaquepsoriasis.

The PGA scale in its typical use, is a 7-point scale ranging from clearto severe.

Severe Very marked plaque elevation, scaling, and/or erythema Moderateto Severe Marked plaque elevation, scaling, and/or erythema ModerateModerate plaque elevation, scaling, and/or erythema Mild to moderateIntermediate between moderate and mild Mild Slight plaque elevation,scaling, and/or erythema Almost clear Intermediate between mild andclear Clear No signs of psoriasis

One embodiment of the invention is a percent of patients achieving a 50%or a 75% reduction in PASI score (PAST 50 or PASI 75) achieved by usinga topical emulsion composition as described herein. This may be astandalone clinical endpoint, or may be used in combination with thepatient also reaching a PGA score of 0 or 1 (clear or almost clear) at adefined time point, such as at 8, 12 weeks, 16 weeks, 20, or 24 weeks,or greater than 24 weeks of treatment. As a degree of measurement ofseverity, the patient will most likely have started with a PGA score of≥4 at baseline for purposes herein, e.g. one with moderate to severeplaque psoriasis.

One embodiment of the invention is a method of obtaining optimal dosingfor the treatment of psoriasis in a patient in need thereof, the methodcomprising administering to said patient a topical pharmaceuticalemulsion composition comprising an effective amount of3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant, andan antioxidant, wherein the emulsion composition is homogenous, andwherein the dosing continues until the patient achieves a PGA score ofclear or almost clear is reached. In one embodiment, the course oftreatment is 28 weeks or less in duration of treatment, or is 21 weeksor less, or is 16 weeks or less in duration of treatment, or is 12 weeksor less in duration of treatment. In one embodiment, the time to relapsepost treatment is 3 months or greater. In another embodiment, the timeto relapse post treatment is 6 months or greater. In one embodiment ofthe invention the time to relapse is not influenced by the duration oftreatment.

Another embodiment of the invention is a method for reducing the time toachieving a >50% improvement in PGA scores of clear or almost clear or a2-point reduction in PGA score in a patient with psoriasis in needthereof, the method comprising administering to said patient a topicalpharmaceutical emulsion composition comprising an effective amount of3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant, andan antioxidant, and wherein the emulsion composition is homogenous. Inone embodiment, the time to achievement of the 50% reduction is at 12weeks. In another embodiment, the time to achievement of the 50%reduction is at 8 weeks. In one embodiment, the reduction of time may becompared to administration of a suitable comparator such as formulation1/la or 12 (of comparable % w/w active).

Alternatively, there is method is achieving a 50% or 75% reduction inPASI score in a patient with psoriasis in need thereof, the methodcomprising administering to said patient a topical pharmaceuticalemulsion composition comprising an effective amount of3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant, andan antioxidant, and wherein the emulsion composition is homogenous.

In one embodiment, the course of treatment is 28 weeks or less induration of treatment, or is 21 weeks or less, or is 16 weeks or less induration of treatment, or is 12 weeks or less in duration of treatment.In one embodiment, the time to relapse post treatment is 3 months orgreater. In another embodiment, the time to relapse post treatment is 6months or greater. In one embodiment of the invention the time torelapse is not influenced by the duration of treatment. A comparatorformulation would be formulation 1/la. In one embodiment the time toachievement of the 50% reduction is at 12 weeks. In another embodimentthe time to achievement of the 50% reduction is at 8 weeks.

In another embodiment there is a method for reducing the time toachieving a >50% improvement in PGA scores of clear or almost clear or a2-point reduction in PGA score and a PASI 50 or PASI 75 reduction in apatient with psoriasis in need thereof, comprising administering to saidpatient a topical pharmaceutical emulsion composition comprising aneffective amount of 3,5-Dihydroxy-4-isopropyl-trans-stilbene or apharmaceutically acceptable salt thereof, an oil phase, a water phase, asurfactant, and an antioxidant, and wherein the emulsion composition ishomogenous. In one embodiment, the PASI score is a PASI 75. In anotherembodiment, the patient achieves a PGA score of clear or almost clear.

In another embodiment there is a method of improving the time toreaching a PASI 50 or PASI 75 score in a person affected in a personwith psoriasis, the method comprising administering to said person atopical pharmaceutical emulsion composition comprising an effectiveamount of 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant, andan antioxidant, and wherein emulsion composition is homogenous. In oneembodiment, the time to reach a PASI 50 is at 16 weeks, or 12 weeks, orat 8 weeks. In another embodiment, the time to reach a PASI 70 is at 16weeks, or 12 weeks, or at 8 weeks. A suitable comparator formulationwould be formulation 1/la or 12 (of comparable % w/w active).

According to an embodiment, the invention provides a method of treatinga dermatological condition or disorder in a patient in need thereof, themethod comprising administering to said patient a topical pharmaceuticalemulsion composition comprising an effective amount of3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant, andan antioxidant, and wherein the emulsion composition is homogenous. Inanother embodiment, the 3,5-Dihydroxy-4-isopropyl-trans-stilbene orpharmaceutically acceptable salt thereof is solubilized in the oil phaseof the emulsion composition. In another embodiment, if the oil phasecomprises mineral oil or petrolatum, then a second oil phase componentis present, and if the oil phase contains both mineral oil andpetrolatum then a third oil phase component is present.

Another aspect of the invention is the use of a topical pharmaceuticalemulsion composition comprising an effective amount of the activeingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or apharmaceutically acceptable salt thereof, an oil phase, a water phase, asurfactant, and an antioxidant, and wherein the emulsion composition ishomogenous, in the manufacture of a medicament for the treatment ofinflammatory skin diseases or disorders in a patient. In one embodiment,the active ingredient is solubilized in the oil phase of the emulsioncomposition. In another embodiment, if the oil phase comprises mineraloil or petrolatum, then a second oil phase component is present, and ifthe oil phase contains both mineral oil and petrolatum then a third oilphase component is present. In one embodiment, the disease or disorderis atopic dermatitis, psoriasis or acne.

The compositions of the present invention may be used in a veterinarysetting or in a medical setting, topically. It is recognized that thepatient or subject may be an animal, a domestic animal, such as amammal, including horses, cows, pigs, sheep, poultry, fish, cats, dogsand zoo animals. In one embodiment, the patient is an animal. In anotherembodiment, the patient is a mammal. In another embodiment, the mammalis a human. In another embodiment, the human is an adult, or a pediatricpatient. In one embodiment, the pediatric patient is a child. In anotherembodiment, the pediatric patient is 3 months to 2 years of age andolder.

In one embodiment, the dermatological condition or disorder for whichtreatment is sought is an inflammatory skin disease (e.g., a chronicinflammatory skin disease such as dermatitis (e.g., atopic dermatitis,contact dermatitis, eczematous dermatitis, or seborrhoic dermatitis),acne, psoriasis, rosacea, or aging skin.

In some aspects, the dermatological condition or disorder is selectedfrom the group for the treatment of a skin disease, wherein the skindisease comprises a skin disorder of persistent inflammation, cellkinetics, and differentiation (e.g., psoriasis, psoriatic arthritis,exfoliative dermatitis, Pityriasis rosea, lichen planus, lichen nitidus,or porokeratosis); a skin disorder of epidermal cohesion, vesicular andbullous disorders (e.g., pemphigus, bulluous pemphigoi, epidermamolysisbullosa acquisita, or pustular eruptions of the palms or soles); a skindisorder of epidermal appendages and related disorders (e.g., hairdisorders, nails, rosacea, perioral dermatitis, or follicularsyndromes); a skin disorder such as an epidermal and appendageal tumors(e.g., squamous cell carcinoma, basal cell carcinoma, keratoacanthoma,benign epithelial tumors, or merkel cell carcinoma); a disorder ofmelanocytes (e.g., pigmentary disorders, albinism, hypomelanoses andhypermelanoses, melanocytic nevi, or melanoma); a skin disorder ofinflammatory and neoplastic disorders of the dermis (e.g., erythemaelavatum diutinum, eosinophils, granuloma facilae, pyoderma gangrenosum,malignant atrophic papulosis, fibrous lesions of dermis and soft tissue,or Kaposi sarcoma); a disorder of the subcutaneous tissue (e.g.,panninculitis or lipodystrophy); a skin disorder involving cutaneouschanges of altered reactivity (e.g., urticaria, angiodererma,graft-vs-host, allergic contact dermatitis, autosensitizationdermatitis, atopic dermatitis, or seborrheic dermatitis); a skin changedue to mechanical and physical factors (e.g., thermal injury, radiationdermatitis, corns, or calluses); photodamage (e.g., acute and chronic UVradiation, or photosensitization); or a skin disorder due to microbialagents (e.g., leprosy, lyme borreliosis, onychomycosis, tinea pedra,rubella, measles, herpes simplex, EBV (Epstein-Barr virus), HPV (Humanpapillomavirus) (e.g., HPV6 &7), warts, or prions).

In one embodiment, the inflammatory disorder is selected from the groupconsisting of psoriasis, and atopic dermatitis and acne. In anembodiment, the dermatological condition or disorder is psoriasis. Inanother embodiment, the dermatological condition or disorder is atopicdermatitis. In another embodiment, the dermatological condition ordisorder is acne.

Definitions

The phrase “therapeutically effective amount” or “effective amount” isused herein to refer to an amount of the active ingredient sufficient tohave a therapeutic effect upon administration, e.g. that amount whichwill cause an improvement or change in the condition for which it isapplied when applied to the affected area repeatedly over a period oftime. Effective amounts will vary with the particular condition beingtreated, the severity of the condition, the duration of the treatment,the stage of advancement of the condition, the body surface areaaffected with the clinical condition, and the specific components of thecomposition. An effective amount of the active ingredient for treatmentof a condition or disorder can be determined by standard clinicaltechniques. Appropriate amounts in any given instance will be readilyapparent to those skilled in the art or capable of determination byroutine experimentation. The compositions are generally applied intopical manner to the affected area, i.e. localized application to theskin region where the clinical abnormality is manifest.

Concentrations, amounts, solubilities, and other numerical data may bepresented herein in a range format. It is to be understood that suchrange format is used merely for convenience and brevity and should beinterpreted flexibly to include not only the numerical values explicitlyrecited as the limit of the range, but also to include all theindividual numerical values or sub-ranges encompassed within that rangeas if each numerical value and sub-range is explicitly recited. Allnumbers expressing quantities, percentages or proportions, and othernumerical values used in the specification, are to be understood asbeing modified in all instances by the term “about”.

For example, a concentration range of 0.1 to 5 ng/ml should beinterpreted to include not only the explicitly recited concentrationlimits of 0.1 ng/ml and 5 ng/ml but also to include individualconcentrations such as 0.2 ng/ml, 0.8 ng/ml, 1.0 ng/ml 2.2 ng/ml, 3.6ng/mol, and sub-ranges such as 0.3-2.5 ng/ml, 1.8-3.2 ng/ml, etc. Thisinterpretation should apply regardless of the breadth of the range orthe characteristic being described.

The terms “administering” and “administration” are used herein to meanany method which in sound medical practice delivers the pharmaceuticalemulsion composition to a patient in such a manner as to provide thedesired therapeutic effect.

As used herein, “topical” administration of the pharmaceutical emulsioncomposition refers to application to and diffusion through the stratumcorneum, including application to psoriatic lesions and broken skin.

As used herein, in the in vitro skin penetration studies the term“epidermis” includes the stratum corneum and tissue or layers down tothe basement membrane, as isolated by heat separation treatment.

As used herein, in the in vitro skin penetration studies with ex-vivohuman abdominal skin dermatomed at a thickness of 500 microns (+/−100microns); the terms “epidermis” is the top/superficial layer obtained byheat separation procedure, and the term “dermis” is the underlying layer(after a washing/tape striping procedure).

The terms “treatment” or “treating” of a dermatological condition ordisorder encompasses alleviation of at least one symptom thereof, areduction in the severity thereof, or the delay, prevention orinhibition of the progression thereof. Treatment need not mean that thecondition or disorder is totally cured. A useful pharmaceutical emulsioncomposition herein need only to reduce the severity of the condition ordisorder, reduce the severity of symptoms associated therewith, provideimprovement to a patient's quality of life, or delay, prevent or inhibitthe onset of the condition or disorder. A treatment need not beeffective in every member of a population, e.g. a population of patientswith atopic dermatitis, to have clinical utility, as is recognized inthe medical and pharmaceutical arts.

The term “pharmaceutically acceptable salt thereof” refers to salts thatare safe and effective for topical use in the patient and possess thedesired pharmaceutical activity. Such salts include salts formed when anacidic proton is replaced with a metal ion (e.g. alkali metal ion,alkaline earth metal ion, or aluminum ion).

The terms “pharmaceutically acceptable” and “dermatologicallyacceptable” mean approvable by a regulatory agency or listed in aPharmacopeia or other generally recognized guide for use in animals, andmore particularly in humans.

As used herein, the term “skin penetration” refers to the diffusion ofthe 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof through the stratum corneum and into theepidermis and/or dermis of the skin.

As used herein, “patients” includes human patients, including adult,teens and children (e.g. pediatric patients). A pediatric patient caninclude teenagers under the age of 18. A child for purposes herein isunder the age of 12.

As used herein, “solublize” means dissolved in a particular phase in anamount ≥50% w/w, or ≥60% w/w, or ≥70% w/w, or ≥80% w/w, or ≥90% w/w or≥95% w/w, based on the percent by weight of the final compositionprepared.

As used herein, “homogenous” means a uniform dispersal of one phasewithin the other. In the instance of an o/w emulsion it is the uniformdispersal of the oil phase within the water phase.

Any concentration range, percentage range or ratio range recited hereinis to be understood to include concentrations, percentages or ratios ofany integer within that range and fractions thereof, such as one tenthand one hundredth of an integer, unless otherwise indicated.

Unless otherwise indicated, all percentages are based on the percent byweight of the final composition prepared, and all totals equal 100% byweight.

It should be understood that the terms “a” and “an” as used herein referto “one or more” of the recited components. It will be clear to one ofordinary skill in the art that the use of the singular includes theplural unless specifically stated otherwise.

Throughout the application, descriptions of various embodiments use“comprising” language, however in some specific instances, an embodimentcan alternatively be described using the language “consistingessentially of” or “consisting of”.

“Substantially free” of a specified component refers to a compositionwith less than about 1% by weight of the specified component. “Free” ofa specified component refers to a composition where the specifiedcomponent is absent.

As the biological profile, or the pK/pD of3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt, depends on the absence of degradation products anddelivery of the active ingredient to the appropriate layers of the skinin efficacious amounts, compositions such as described herein offerpatients a novel therapeutic treatment option for various inflammatoryskin conditions.

Other terms used herein are intended to be defined by their well knownmeanings in the art. The examples set forth below are illustrative ofthe present invention and are not intended to limit, in any way, thescope of the present invention. The following examples illustrate theinvention. These examples are not intended to limit the scope of thepresent invention, but rather to provide guidance to the skilled artisanto prepare and use the compounds, compositions, and methods of thepresent invention.

While particular embodiments of the present invention are described, theskilled artisan will appreciate that various changes and modificationscan be made without departing from the spirit and scope of theinvention.

EXAMPLES Example 1—Preparation of a Cream Comprising 0.5 w/w3,5-dihydroxy-4-isopropyl-trans-stilbene

The following cream composition was prepared:

TABLE 1 Formulation Number 1 1(a) Ingredient % w/w % w/w Active PhaseActive ingredient 0.50 1.00 Propylene glycol 10.00 10.00 Diethyleneglycol monoethyl 2.00 2.00 ether Polysorbate 80 1.00 1.00 Water PhasePurified water 53.09 52.59 Sodium acetate 0.51 0.51 Glacial acetic acid0.10 0.10 Methylparaben 0.18 0.18 Propylparaben 0.02 0.02 Oil phaseEmulsifying Wax, BP 7.20 7.20 White petrolatum 17.00 17.00 Mineral oil6.00 6.00 Steareth 2 1.50 1.50 Steareth 20 0.90 0.90 100.00 100.00

Due to chemical degradation of the active ingredient observed uponstability testing of this formulation, alternative formulations werethen prepared where an antioxidant was added, and alternativepreservative and buffer systems were used. Also, alternatively Crodex™can be replaced with Polawax™. See Examples 2-4 below.

Example 2—Preparation of Cream Compositions Comprising 0.5% w/w3,5-Dihydroxy-4-isopropyl-trans-stilbene

The following cream compositions were subsequently prepared:

TABLE 2 Formulation Number 2 3 4 5 Ingredient % w/w % w/w % w/w % w/wActive Phase Active ingredient 0.50 0.50 0.50 0.50 Polysorbate 80 1.00 —— 1.00 Propylene glycol 10.00 10.00 10.00 10.00 Diethylene glycolmonoethyl 2.00 2.00 2.00 2.00 ether Water Phase Purified water 53.2349.23 53.43 53.23 Sodium citrate dihydrate 0.19 0.19 0.19 0.19 Citricacid 0.08 0.08 0.08 0.08 Di sodium EDTA 0.10 0.10 0.10 0.10 Oil PhasePetrolatum white 17.00 17.00 17.00 17.00 Light mineral oil 6.00 6.006.00 6.00 Steareth 2 1.50 1.50 1.50 1.50 Steareth 20 0.90 0.90 0.90 0.90Antioxidant 0.05 0.05 0.05 0.05 Preservative 0.25 0.25 0.25 0.25Non-ionic emulsifying wax 7.20 12.20 8.00 — Sodium cetostearyl sulphate— — — 7.20 and cetearyl alcohol (Kolliphor CS A) 100.00 100.00 100.00100.00

Example 3—Additional Cream Compositions Comprising 0.5% w/w3,5-Dihydroxy-4-isopropyl-trans-stilbene

TABLE 3 Formulation Number 6 7 8 9 Ingredient % w/w % w/w % w/w % w/wActive Phase Active ingredient 0.50 0.50 0.50 0.50 Polysorbate 80 2.881.00 — 1.00 Polysorbate 20 — — 2.88 — Propylene glycol 10.00 10.00 10.0010.00 Diethylene glycol monoethyl 2.00 2.00 2.00 2.00 ether Water PhasePurified water 54.23 59.43 54.23 52.93 Sodium citrate dihydrate 0.190.19 0.19 0.19 Citric acid 0.08 0.08 0.08 0.08 Disodium EDTA 0.10 0.100.10 0.10 Oil Phase Petrolatum white 17.00 17.00 17.00 17.00 Lightmineral oil 6.00 6.00 6.00 6.00 Steareth 2 1.50 1.50 1.50 1.50 Steareth20 0.90 0.90 0.90 0.90 Propyl gallate 0.05 0.05 0.05 0.05 Benzoic Acid0.25 0.25 0.25 0.25 Cetearyl alcohol 4.32 — 4.32 — Glyceryl stearate +PEG 100 — — — 7.50 stearate PEG 40 hydrogenated castor oil — 1.00 — —100.00 100.00 100.00 100.00

Example 4—Further Cream Compositions Comprising 0.5% w/w3,5-Dihydroxy-4-isopropyl-trans-stilbene

Based on the findings from Examples 2 and 3, Formulations 10-14 wereselected for further development. Formulations 10-14 are the same aseach other with the exception that different levels of active ingredientare present (ranging from 0%-2% w/w) and the water level is adjustedaccordingly.

TABLE 4 Formulation Number 12 10 11 (tergus) 13 14 Ingredient % w/w %w/w % w/w % w/w % w/w Active Phase Active ingredient 0.00 0.10 0.50 1.002.00 Polysorbate 80 1.50 1.50 1.50 1.50 1.50 Propylene glycol 10.0010.00 10.00 10.00 10.00 Diethylene glycol 2.00 2.00 2.00 2.00 2.00monoethyl ether Water Phase Purified water 53.18 53.08 52.68 52.18 51.18Sodium citrate 0.19 0.19 0.19 0.19 0.19 Citric acid 0.08 0.08 0.08 0.080.08 Disodium EDTA 0.10 0.10 0.10 0.10 0.10 Oil Phase BHT 0.10 0.10 0.100.10 0.10 Benzoic Acid 0.25 0.25 0.25 0.25 0.25 Non-ionic emulsifying7.20 7.20 7.20 7.20 7.20 wax Petrolatum white 16.50 16.50 16.50 16.5016.50 Light mineral oil 6.00 6.00 6.00 6.00 6.00 Steareth 2 1.80 1.801.80 1.80 1.80 Steareth 20 1.10 1.10 1.10 1.10 1.10 100.00 100.00 100.00100.00 100.00

Example 5—Method of Preparation

The cream compositions described in Examples 1-4 were prepared using thefollowing general method:

Oil Phase:

1. To a suitably sized vessel, add oil phase ingredients (e.g. whitepetrolatum, mineral oil, steareth 2 and steareth 20), initiate mixingand heat to 70-80° C.

2. Once the oil phase is at 70-80° C., slowly add Polawax™, Crodex orcetearyl alcohol (as the case may be). Mix until all materials aremelted/dissolved and the oil phase is uniform in appearance.

Active Phase:

3. To another suitably sized vessel, add active phase ingredients (e.g.propylene glycol and diethylene glycol monoethyl ether). Heat to 50-60°C. while mixing.

4. Once the temperature has been reached, slowly add the activeingredient to the active phase while mixing. Maintain temperature at50-60° C. and mix until uniform and free of undissolved particles andthe active phase is uniform in appearance.

Water Phase:

5. Add water phase ingredients to the main mixing vessel (e.g. water andbuffer). Begin mixing and heat to 70-80° C. Mix until all materials arefully dissolved and the water phase is uniform in appearance.

Emulsification:

6. Once the water and oil phases are free of undissolved particles,uniform in appearance and at 70-80° C., slowly vacuum transfer the oilphase into the main vessel containing the water phase. Scrape down theoil phase vessel and transfer to the main vessel.

7. Once the transfer and scrape-down are complete, maintain mixersettings and mix for 5-10 minutes while maintaining product temperaturebetween 70-80° C. Verify the product is uniform in appearance.

8. Once uniform, maintain mixing and cool to 50-60° C.

9. Once the product and active phase temperatures are at 50-60° C.,increase mixing and slowly vacuum transfer the active phase into themain vessel. Scrape down and rinse the active phase vessel using thereserved propylene glycol and transfer to the main vessel.

10. Once the transfer and scrape-down are complete, increase vacuumlevel and maintain mixer settings and mix for 5-10 minutes whilemaintaining product temperature between 50-60° C. Verify the product isuniform in appearance.

11. Once mixing is complete, maintain mixing and cool the batch to 30°C. (25-35° C.).

12. Once the temperature has been reached, reduce mixing and cool thebatch to <25° C.

13. Once the product temperature is <25° C., mix for 15 minutes at highspeed. Maintain product temperature at <25° C.

14. Once mixing is complete, reduce mixing speeds and verify the productis uniform in appearance. If necessary, cool the product to <25° C.prior to initiating product discharge.

15. Once uniform and the product temperature is <25° C., discharge theproduct into appropriate storage containers taking samples as necessary.

An alternative process where the water phase is added to the oil phase(i.e. the opposite of the above-mentioned process) resulted in a productwith an unsatisfactory physical appearance and inferior chemicalstability.

Example 6—Chemical and Physical Stability

Samples of Formulations 2-5 were stored at 25, 30 and 40° C. for 3months and were subjected to visual analysis. Formulations 2-4 presentedno discoloration or physical separation over the 3 month period.Formulation 5 however had signs of non-homogeneity.

The samples were also subjected to chemical stability analysis by HPLCusing the following conditions:

-   Zorbax Bonus reverse phase column: 150×4.6 mm, 3.5 μm particle size    with 4.0 mm guard frit Column temp: 25° C.-   Autosampler temp: ambient-   Flow rate: 1.0 ml/min-   Injection volume: 15 μl-   Detection: 235 nm-   Run time: 50 minutes-   Mobile Phase A: 0.1% TFA in water-   Mobile Phase B: Acetonitrile

TABLE 5 HPLC elution gradient Time (minutes) % B 0 5 40 100 45 100 45.15 50 5

Formulations 2-5 met chemical stability specifications when stored atstandard ICH conditions for up to 3 months. Formulations 6-9 displayedsimilar chemical and physical stability. Based on these findings,Formulations 10-14 were selected for further development. However,during process development of Formulations 10-14 it was observed frommicroscopic analysis that the emulsion structure of these formulationswas non-uniform and had wax-like material present. The non-uniformemulsion is illustrated in FIG. 1 and was determined to be dependent onthe concentration of the active ingredient. In other words, there was nosuch observation in Formulation 10 (placebo) and increased levels ofheterogeneity were observed with increasing levels of active ingredient.

To identify which semi-solid ingredient is responsible for forming thenon-uniform emulsion, experiments were conducted where each semi-solidingredient was systematically substituted as follows:

TABLE 6 Remove Substitute Emulsifying wax NF Water Steareth-2 &Steareth-20 Water White petrolatum Mineral oil White petrolatum WaterEmulsifying wax NF & white Water Petrolatum

The formulation that was free of petrolatum was observed to have auniform emulsion. Additional characterization was conducted using hotstage optical microscopy, XRD, IR microscopy and fluorescent microscopy.These techniques confirmed that the wax-like material was comprised ofpetrolatum and was a function of the concentration of the activeingredient present. These observations suggested that the petrolatum wasnot adequately emulsified and that the active ingredient was notsolubilized in either the water phase or the oil phase of the emulsion.

Example 7—Development of Final Physically and Chemically Stable CreamFormulation Comprising 0.5% w/w 3,5-Dihydroxy-4-Isopropyl-Trans-Stilbenefor Clinical Development

The solubility of the active ingredient in different solvents wasdetermined. The active ingredient was observed to have good solubilityin medium chain triglycerides (MCT), which was chosen to replace thewhite petrolatum and mineral oil in the oil phase of the emulsioncomposition. The following formulations were prepared with 5%, 10%, 15%and 20% MCT (Formulations 15-18). Two formulations (Formulations 19 and20) were also prepared where Polawax (a proprietary blend of cetostearylalcohol and emulsifiers) was replaced with cetostearyl alcohol andadditional emulsifier.

TABLE 7 Formulation Number 15 16 17 18 19 20 Ingredient % w/w % w/w %w/w % w/w % w/w % w/w Water Phase Purified water 53.68 58.68 65.18 70.1863.38 65.18 Sodium citrate 0.19 0.19 0.19 0.19 0.19 0.19 Citric acid0.08 0.08 0.08 0.08 0.08 0.08 Disodium 0.10 0.10 0.10 0.10 0.10 0.10EDTA Oil Phase Active 2.00 2.00 0.50 0.50 0.50 0.50 ingredient Propylene10.00 10.00 10.00 10.00 10.00 10.00 glycol Diethylene 2.00 2.00 2.002.00 2.00 2.00 glycol monoethyl ether BHT 0.10 0.10 0.10 0.10 0.10 0.10Benzoic Acid 0.25 0.25 0.25 0.25 0.25 0.25 Polawax 7.20 7.20 7.20 7.20 —— Cetostearyl — — — — 7.20 5.40 alcohol MCT 20.00 15.00 10.00 5.00 10.0010.00 Polysorbate 80 1.50 1.50 1.50 1.50 2.10 2.10 Steareth 2 1.80 1.801.80 1.80 2.50 2.50 Steareth 20 1.10 1.10 1.10 1.10 1.60 1.60 100.00100.00 100.00 100.00 100.00 100.00

Formulations 15-20 were subjected to microscopic analysis. All sixformulations were found to be homogeneous and the dispersed oil phasehad a small particle size and a uniform emulsion was observed. Thedifference in the appearance of a formulation with 10% MCT as the oilphase versus a formulation with larger amounts of white petrolatum andmineral oil as the oil phase is illustrated in FIG. 2. Without wishingto be bound by theory, it is thought that because the active ingredientis amphiphilic it has the potential to destabilize the emulsion,particularly when appropriate solvent selection is not made. It isthought that by using the appropriate solvent for the active ingredientin the oil phase, a more stable emulsion may be obtained.

Formulation 17 (0.5% active ingredient) was prepared, along withequivalent formulations containing 1% active ingredient, 2% activeingredient (Formulations 21 and 22, respectively) and 3% activeingredient (Formulation 26). Alternative formulations where 7.2% Polawaxwas replaced with 5.90% cetostearyl alcohol and increased surfactantlevels were also prepared (Formulations 23 and 24). A variant ofFormulation 17 but with 0.1% active ingredient is shown as Formulation25. Formulation 17 met all chemical and physical stabilityspecifications when stored at standard ICH conditions for up to 6months. Thus one embodiment of the invention is a chemically andphysically stable pharmaceutical emulsion composition when stored atstandard ICH conditions for up to 6 months comprising the activeingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or apharmaceutically acceptable salt thereof, an oil phase, a water phase, asurfactant, and an antioxidant, and wherein the active is solubilized inthe oil phase of the emulsion composition. Another embodiment of theinvention is a chemically and physically stable pharmaceutical emulsioncomposition when stored at standard ICH conditions for up to 6 monthscomprising the active ingredient3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceuticallyacceptable salt thereof, an oil phase, a water phase, a surfactant, andan antioxidant, and wherein the emulsion is homogenous. In anotherembodiment, the active is solubilized in the oil phase of the emulsioncomposition. In another embodiment, the average droplet size of thediscontinuous phase is 1 micron or less.

Additional formulations were also made with changes to the co-solvents,e.g. Formulations 27 to 29. These data suggest that propylene glycol orTranscutol are not needed for physical stability of formulations, thusproviding opportunities for alternative solvents for solubilization ofthe active ingredients to be used.

The formulations are shown in Table 8 below:

TABLE 8 Formulation Number 17 21 22 23 24 25 26 27 28 29 Ingredient %w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w Purified water65.18 64.68 63.68 63.18 61.18 65.58 62.68 75.18 67.18 77.18 Sodiumcitrate 0.19 0.19 0.19 0.19 0.19 0.19 0.19 0.19 0.19 0.19 Citric acid0.08 0.08 0.08 0.08 0.08 0.08 0.08 0.08 0.08 0.08 Disodium 0.10 0.100.10 0.10 0.10 0.10 0.10 0.10 0.10 0.10 EDTA Active 0.50 1.00 2.00 2.004.00 0.10 3.00 0.50 0.50 0.50 Ingredient Propylene 10.00 10.00 10.0010.00 10.00 10.00 10.00 — 10.00 — glycol Diethylene 2.00 2.00 2.00 2.002.00 2.00 2.00 2.00 glycol monoethyl ether BHT 0.10 0.10 0.10 0.10 0.100.10 0.10 0.10 0.10 0.10 Benzoic Acid 0.25 0.25 0.25 0.25 0.25 0.25 0.250.25 0.25 0.25 Emulsifying 7.20 7.20 7.20 — — 7.20 7.20 7.20 7.20 7.20wax, NF Cetostearyl — — — 5.90 5.90 — — ″ ″ ″ alcohol MCT 10.00 10.0010.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 Polysorbate 1.50 1.501.50 2.10 2.10 1.50 1.50 1.50 1.50 1.50 80 Steareth 2 1.80 1.80 1.802.50 2.50 1.80 1.80 1.80 1.80 1.80 Steareth 20 1.10 1.10 1.10 1.60 1.601.10 1.10 1.10 1.10 1.10 100.00 100.00 100.00 100.00 100.00 100.00100.00 100.00 100.00 100.00

Example 8—Method of Preparation of Final Formulations

The cream compositions described in Example 7 were prepared using thefollowing general method:

Oil Phase:

1. To a suitably sized vessel, add oil phase ingredients (e.g. MCT,Polawax™, benzoic acid, BHT, propylene glycol, diethylene glycolmonoethyl ether, polysorbate 80, steareth 2, steareth 20 and the activeingredient), initiate mixing and heat to 70-80° C., continue mixinguntil the active ingredient is dissolved and the phase is uniform inappearance.

Water Phase:

2. Add water phase ingredients to the main mixing vessel (e.g. water andsodium citrate, citric acid and Edetate disodium). Begin mixing and heatto 70-80° C. Mix until all materials are fully dissolved and the waterphase is uniform in appearance.

Emulsification:

3. Once the water and oil phases are free of undissolved particles,uniform in appearance and at 70-80° C., slowly vacuum transfer the oilphase into the main vessel containing the water phase. Scrape down theoil phase vessel and transfer to the main vessel.

4. Once the transfer and scrape-down are complete, maintain mixersettings and mix for 5-10 minutes while maintaining product temperaturebetween 70-80° C. Verify the product is uniform in appearance.

5. Transfer batch to holding vessel. Cool.

Thus, another embodiment of the present invention is a method of makingan emulsion composition comprising

-   -   i) mixing and heating the oil phase ingredients and the active        ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a        pharmaceutically acceptable salt thereof until dissolved;    -   ii) mixing the water phase ingredients until fully dissolved;    -   adding the oil phase ingredient of step (i) and the water phase        ingredients of step (ii) and mixing until uniform in appearance.        In one embodiment, the resulting emulsion composition is        homogenous. In another embodiment the active ingredient is        solubilized in the oil phase. In another embodiment, the average        droplet size of the discontinuous phase is about 35 microns or        less. In another embodiment, the average droplet size of the        discontinuous phase is less than about 25 microns. In another        embodiment, the average droplet size of the discontinuous phase        is less than about 15 microns. In another embodiment, the        average droplet size of the discontinuous phase is less than        about 10 microns. In another embodiment, the average droplet        size of the discontinuous phase is less than about 5 microns. In        another embodiment, the average droplet size of the        discontinuous phase is about or is less than about 1 micron. In        another embodiment, the average droplet size of the        discontinuous phase is about 0.5 microns. In another embodiment,        the average droplet size of the discontinuous phase is from        about 0.05 to about 35 microns. In another embodiment, the        average droplet size of the discontinuous phase is from about        0.05 to about 5 micron. In another embodiment, the average        droplet size of the discontinuous phase is from about 0.05 to        about 1 micron. In another embodiment, the average droplet size        of the discontinuous phase is from about 0.1 to about 0.75        microns. In another embodiment, the average droplet size of the        discontinuous phase is from about 0.05 to about 35 microns. In        another embodiment, the average droplet size of the        discontinuous phase (D50) is less than 5 microns. In another        embodiment, the average droplet size of the discontinuous phase        (D50) is less than 1 micron.

In another embodiment, there is a method of making an emulsioncomposition comprising

-   -   i) mixing and heating the oil phase ingredients and the active        ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a        pharmaceutically acceptable salt thereof until dissolved;    -   ii) mixing the water phase ingredients until fully dissolved;        -   adding the oil phase ingredient of step (i) and the water            phase ingredients of step (ii) and mixing until uniform in            appearance, and the emulsion is homogenous and optionally            has an average droplet size of the oil phase/discontinuous            phase (D50) of less than 5 microns.

Example 9—Further Cream Compositions Comprising 1.0% w/w3,5-Dihydroxy-4-isopropyl-trans-stilbene

To assist in identification of the semi-solid ingredients responsiblefor forming the non-uniform emulsion, additional experiments wereconducted wherein petrolatum was kept in the formulation, mineral oilwas removed and replaced by medium chain triglycerides (MCT) in the oilphase of the emulsion composition (see Table 9). In general, thevariable for Formulations 30-32 was the % amount of petrolatum and thesubsequent water concentrations. Formulations 33 and 37 demonstrate alower level of petrolatum (4% and 2%) with 10% MCT. Formulation 34demonstrates MCT and mineral oil together. Formulation 35 and 36demonstrates a low level of mineral oil and petrolatum together withMCT, and lastly Formulations 38 and 39 demonstrate a low level ofmineral oil and petrolatum together without MCT. Non-uniform emulsioncharacteristics were seen in formulations 34-37 of varying size.Formulations containing lower levels of petrolatum still lead tonon-uniform emulsion characteristics with the active ingredient whichmight still be stable but are unknown at this time. Notably, mineral oilcan be added in combination with MCT in the formulations.

TABLE 9 Formulation Number 30 31 32 33 34 35 36 37 38 39 40 Ingredient %w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w WaterPhase Purified water 48.18 52.68 56.68 60.68 57.75 56.75 60.67 59.6769.18 66.38 65.18 Sodium citrate 0.19 0.19 0.19 0.19 0.19 0.19 0.19 0.190.19 0.19 0.19 Citric Acid 0.08 0.08 0.08 0.08 0.09 0.09 0.09 0.09 0.080.08 0.08 (anhydrous or monohydrate) Disodium 0.10 0.10 0.10 0.10 0.090.09 0.09 0.09 0.10 0.10 0.10 EDTA Oil Phase Active 1.00 1.00 1.00 1.002.00 2.00 2.00 2.00 0.50 0.50 0.50 Ingredient Propylene 10.00 10.0010.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 glycol Diethylene2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00 glycol monoethylether BHT 0.10 0.10 0.10 0.10 0.10 0.10 0.10 0.10 0.10 0.10 0.10 BenzoicAcid 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.10 0.10 0.10 Emulsifying7.20 7.20 7.20 7.20 7.20 7.20 7.20 7.20 7.20 10.00 7.20 wax, NF White16.50 12.00 8.00 4.00 4.00 2.00 4.00 3.00 3.00 — Petrolatum MCT 10.0010.00 10.00 10.00 10.00 10.00 10.00 10.00 Mineral Oil — — — — 6.00 3.001.00 — 3.00 3.00 10.00 Polysorbate 1.50 1.50 1.50 1.50 1.50 1.50 1.501.50 1.50 1.50 1.50 80 Steareth 2 1.80 1.80 1.80 1.80 1.80 1.80 1.801.80 1.80 1.80 1.80 Steareth 20 1.10 1.10 1.10 1.10 1.10 1.10 1.10 1.101.10 1.10 1.10 100.0 100.0 100.00 100.0 100.0 100.0 100.0 100.0 100.0100.0 100.0

It has been noted that Example 3 of U.S. Pat. No. 7,868,047 contained anactive in a “Galax” cream base which does not appear to be a compendialnor commercially available base. There a commercial product is availablefrom WellSpring Pharmaceuticals, Fla., USA entitled “Glaxal” cream basethat comprises water, petrolatum, cetearyl alcohol, paraffinum liquidum,cereareth-20, sodium phosphate and p-chloro-m-cresol.

Using Example 3 as a guide, two formulations were made usingtheWellSpring Glaxal base. The active ingredient3,5-Dihydroxy-4-isopropyl-trans-stilbene was dissolved in ethanol andthen added to the Glaxal base while mixing. Mixing was continued for 15min until the formulations looked homogenous and then analyzed withmicroscopy.

Formulation 41 with 1% active ingredient and 42 with 2% activeingredient were made with the following compositions:

Ingredient % w/w 3,5-Dihydroxy-4-isopropyl- 1-2 trans-stilbene Ethanol10 Glaxal base q.s. 100

As evidenced by microscopy, droplet/particle size increases as soon asactive ingredient is added to the base and is dependent on the amount ofactive added. This is similar to observations seen with formulationssimilar to Formululation 12 which also contained both mineral oil andpetrolatum.

Example 10—Effects of the Cream Compositions Comprising3,5-Dihydroxy-4-isopropyl-trans-stilbene on Skin Penetration Properties

The object of this study was to determine the in-vitro skin penetrationof 3,5-Dihydroxy-4-isopropyl-trans-stilbene.

In particular, Formulations 17 and 21-24 were tested for their abilityto deliver the active ingredient into the epidermis and dermis, and werecompared against Formulations 1 and 12.

Briefly, Formulations 1, 12, 17 and 21-24 comprising3,5-Dihydroxy-4-isopropyl-trans-stilbene were evaluated using a skinpenetration assay. This study was designed to determine drug permeationinto the epidermis, dermis and receiving fluid. Freshly excised humanabdominal skin was dermatomed to a thickness of 500±100 μm and mountedon flow-through diffusion cells using donor blocks to provide a leakproof seal, exposing a surface area of 1.0 cm². Diffusion cells wereconnected to multi-channel pumps with a flow rate of approximately 0.6mL/hr with PBS. Each cell was then equilibrated in a heating manifold toensure a skin surface temperature of 32° C. (for at least 30 min priorto dosing). Test articles were applied at a dose of 10 μl per skinsection (10 mg test article/cm²). Test articles were applied to twoseparate donors to capture inter-individual variation and to at leastseven skin sections per donor to capture intra-individual variation. At15 hours post-application, the skin surface was wiped with cotton swabs,and tape-stripped three times to remove any residual test article. Thewashed skin was heat split at the epidermal and dermal junction. Theskin layers were placed in separate homogenization vials and the drugwas extracted. The extraction of active ingredient from separate testarticles served to assess the efficiency of the extraction solvent. Therecovered drug concentrations were used to calculate skin penetrationinto the epidermis and dermis as a percentage of applied doses.3,5-Dihydroxy-4-isopropyl-trans-stilbene was detected using a liquidchromatography/mass spectrometry.

The amount of 3,5-Dihydroxy-4-isopropyl-trans-stilbene delivered intothe epidermis, dermis (15 hours post application) from Formulations 1,12, 17 and 21-24 is shown in FIG. 3.

Error bars represent the standard error of the mean (SEM) of 8 to 14replicates per formulation (four skin donors). Note: Since the dosingarea of the diffusion cell was 1 cm², the amounts of3,5-Dihydroxy-4-isopropyl-trans-stilbene illustrated in FIG. 3 representμg/cm².

When comparing the 0.5% w/w 3,5-Dihydroxy-4-isopropyl-trans-stilbeneformulations, it was observed the amount of3,5-Dihydroxy-4-isopropyl-trans-stilbene delivered into the epidermiswere similar for Formulation 17, Formulation 1 and Formulation 12.However Formulation 17 delivered approximately 3-fold more3,5-Dihydroxy-4-isopropyl-trans-stilbene to the dermis compared toFormulation 12 and Formulation 1. In addition, it was observed from thedata for Formulations 17, 21 and 22 that the active ingredient wasdelivered in a dose dependent manner. Similarly, it was observed fromthe data for Formulations 23 and 24 that the active ingredient wasdelivered in a dose dependent manner.

There appeared to be an inverse relationship in the amount of3,5-Dihydroxy-4-isopropyl-trans-stilbene delivered into the receivingfluid over fifteen hours, where Formulation 17 showed a 2-4-fold loweramount compared to Formulation 12 and Formulation 1. Similar to theamounts delivered to the skin layers (epidermis and dermis), it wasobserved from the data for Formulations 17, 21 and 22 that the activeingredient was delivered in a dose dependent manner into the receivingfluid. Similarly, it was observed from the data for Formulations 23 and24 that the active ingredient was delivered in a dose dependent mannerinto the receiving fluid.

Example 11—Effects of the Cream Compositions Comprising3,5-Dihydroxy-4-isopropyl-trans-stilbene on Skin Deposition

Previous studies, showed Formulation 17 delivered higher amounts of3,5-Dihydroxy-4-isopropyl-trans-stilbene to the dermis with loweramounts partitioning into the receiving fluid compared to Formulation12. To further explore this observation, a study was conducted in humanex vivo skin to measure dermal levels every three hours (0-15 hours) andat 24 hours and compared to the concentrations measured in the receivingfluid.

Formulations 12 and 21 comprising 0.5% and 1.0%3,5-Dihydroxy-4-isopropyl-trans-stilbene respectively were evaluatedusing an ex vivo human skin penetration assay. This study was designedto determine drug permeation into the epidermis, dermis and receivingfluid with more additional sampling for skin deposition. Freshly excisedhuman abdominal skin was dermatomed to a thickness of 500±100 μm andmounted on flow-through diffusion cells using donor blocks to provide aleak proof seal, exposing a surface area of 1.0 cm². Diffusion cellswere connected to multi-channel pumps with a flow rate of approximately0.6 ml/hr with PBS. In order to keep the skin integrity and preventbacterial growth, the seventy two hour study receiving fluid contained1% antibiotic-antimycotic. Each cell was then equilibrated in a heatingmanifold to ensure a skin surface temperature of 32° C. (for at least 30min prior to dosing). Test articles were applied at a dose of 10 μl perskin section (10 mg test article/cm²). Test articles were applied to twoseparate donors to capture inter-individual variation and to at leastseven skin sections per donor to capture intra-individual variation.Receiving fluid was collected hourly for 72 hours as a measurement ofactive ingredient penetrating through the skin. At 3, 6, 9, 12, and 15hours post-application, the skin surface was wiped with a cotton swaband tape-stripped three times to remove any residual test articleconsidered not penetrating the skin. The washed skin was heat split atthe epidermal and dermal junction. The skin layers were placed inseparate homogenization vials and the drug was extracted using an Omnibead homogenizer. The recovered drug concentrations were used tocalculate skin penetration into the epidermis and dermis as a percentageof applied doses. 3,5-Dihydroxy-4-isopropyl-trans-stilbene was detectedusing a liquid chromatography/mass spectrometry method describedpreviously.

Formulation 21 showed the same trend observed previously, where theconcentrations of 3,5-Dihydroxy-4-isopropyl-trans-stilbene delivered tothe dermis were higher compared to Formulations 12. See FIG. 5. Thetrend for increased dermal deposition or tissue residency fromFormulation 21 appeared as early as 3 hours post application andcontinued over the 15 hours of dosing.

Later time points (i.e. greater than 15 hours) were not considered fortissue analysis (epidermis and dermis) as the skin started losing itsintegrity, which could potentially result in inaccurate measured levelsof active ingredient.

The same inverse relationship in the amount of3,5-Dihydroxy-4-isopropyl-trans-stilbene delivered into the receivingfluid was observed, where Formulation 21 showed a 1.4 fold lower amountcompared to Formulation 12 (FIG. 6). This trend for lowered delivery tothe receiving fluid was consistent over the entire 72 hours of dosing asboth formulations appeared to be in a steady state after 12 hours (lagphase). Despite Formulation 21 (1% w/w) having double the concentationof active ingredient as Formulation 12 (0.5 w/w), Formulation 21 was notable to deliver equivalent amounts into the receiving fluid. Thissuggests Formulation 21 is able to alter tissue residence preventing theactive ingredient from partitioning from the skin into the receivingfluid.

In one embodiment of the invention is the use of a formulation such asdescribed above which can provide lower systemic exposure of the activeingredient to the patient during use. In another embodiment, the dosingfrequency to the affected area(s) may be now be dosed less frequentlythan previously envisioned. Application of a composition of the presentinvention may be applied to affected areas twice daily, once daily, onceevery other day; twice weekly; three times weekly, or once weekly, withthe dose represented by any of the embodiments herein. In anotherembodiment, the treatment may be administered in two phases, an initialdosage frequency such as once or twice daily, followed by a maintenancephase, such as every other day; twice weekly; three times weekly, oronce weekly.

Example 12—Biological Activity in Ex Vivo Human Skin from CreamCompositions Comprising 3,5-Dihydroxy-4-Isopropyl-Trans-Stilbene

Target profiling revealed 3,5-Dihydroxy-4-isopropyl-trans-stilbene to bean activator of the AhR pathway in intestinal human colonadenocarcinoma. BioMAP®, a system that can offer physiologicallyrelevant insights about a compound prior to lengthy and expensive animalor clinical studies, confirmed that Ahr is likely to be a primary targetof 3,5-Dihydroxy-4-isopropyl-trans-stilbene.3,5-Dihydroxy-4-isopropyl-trans-stilbene has also been shown to inducethe expression of the AhR target gene, Cyp1A1, in primary humankeratinocytes, and human or rodent leukocytes. A model using freshlyexcised human skin has been developed to explore intrinsic efficacy ofactive ingredients (i.e., target engagement). This model allows topicalformulations to be applied to explore pharmacodynamic activity in theskin. This study compares the biological activity of3,5-Dihydroxy-4-isopropyl-trans-stilbene through Cyp1A1 induction fromFormulations 17, 21 and 22 as compared to Formulation 12.

Tissue Culture Using Static Cells:

Freshly excised healthy human skin was dermatomed to 750 um and cleanedwith antibiotic/antimycotic solution made up as 1% GIBCO™Antibiotic-Antimycotic (100×), 0.1% Gentamicin in 1× Dulbecco'sPhosphate Buffered Saline. Twelve mm diameter biopsies were cut usingdisposable single-use biopsy punches and washed inantibiotic/antimycotic solution for 5-10 minutes. Skin biopsies wereplaced on autoclaved 7 mm (0.38 cm²) unjacketed static cells with 2 mlreceptor volume and leak proof seal was maintained using metal clampsand donor chamber. Receptor chamber was filled with cornification mediausing pastuer pipette to dispense in sampling port. Static cells werethen placed in a humidified incubator at 37° C. Test articles wereapplied topically (to the exposed/dry epidermis) on Day 1. (Day-1).Twenty-four hours later (Day 0), media in the receptor chamber wasreplaced with an activation cocktail designed to stimulate skin-residentimmunocompetent cells. Twenty-four hours later (Day 1) the tissue wasremoved, minced to less than 1×1×1 mm pieces and stored in 10× volume ofRNA later with 300 μl of RNeasy Lysis Buffer supplemented with 1%2-Beta-Mercapto-Ethanol for RNA isolation.

Cornification Media:

Media consisted of 237 ml of Dulbecco's Modified Eagle Medium (DMEM),237 ml Ham's F-12K Medium, 1 ml 90 mM Adenine, 1 mL 0.94M CaCl, 1 ml 10nM Tri-iodothyronine, 1 ml Insulin-Transferrin-Selenium-Ethanolamine(ITS-X) (100×), 5 ml Antibiotic-Antimycotic (100×), 10 ml Fetal BovineSerum (FBS), 5 ml GlutaMAX™ Supplement, 0.1 ml 50 mg/ml Gentamicin.

Activation Cocktail:

An ex vivo human skin target engagement model was originally developedto mimic the pro-inflammatory state of lesional psoriatic skin. Themodel may be found in Smith et al., PLOS ONE, DOI:10.1371/journal.pone.0147979; Feb. 12, 2016 and is referenced herein asthe sRICA (skin-resident immune cell activation) assay. As such, skinresident immunocompetent cells were activated in situ with a combinationof 1 ug/ml purified NA/LE Mouse anti-human CD3, 2 ug/ml CD28, 1 ug/mlanti-human IFN-gamma, 1 ug/ml anti-human IL-4 antibodies and 10 ng/mlrecombinant human (rh) IL-lb/IL-lF2, 10 ng/ml rh IL-6 (R&DSystems, 1ng/ml rh TGF-bl, and rh IL-21. All components incorporated in a singlemixture with the cornification media (i.e., activation cocktail).

RNA Isolation & Quantitation:

Approximately 40 mg of minced tissue was added to homogenization tubescontaining 2.8 and 1.4 mm ceramic beads. The tissue was disrupted usinghigh-throughput bead mill homogenizer machine at 6300 rpm for 30 secondsand 10 cycles with a 2-minute ice break. The homogenate was digested byadding 490 μl of water containing 10 ul Proteinase K at 55° C. for 15minutes. Digested tissue was spun down for 3 minutes at 10,000×g topellet cell debri and the supernantant was used for RNA isolation usingQiagen's Mini RNA Isolation kit according to manufacturer's protocol.Total RNA was quantified using Nanodrop 2000. Isolated RNA (1.4 ug) fromskin tissue was used as a template in a 20 ul PCR volume usingInvitrogen Superscript VILO cDNA Synthesis kit to create cDNA template.The cDNA was diluted 1:25 for subsequent qPCR with the specific TaqManprobe for each gene to be quantified. Life Technologies AVii7 PCRmachine was used for the qPCR 40 amplification cycles. RNA levels ofCyp1A1 relative expression were calculated using the Delta Delta CTformula and normalized to untreated skin sections.

Formulations 17, 21 and 22 and Formulation 12 showed biological activityfor 3,5-Dihydroxy-4-isopropyl-trans-stilbene in human skin as measuredindirectly by Cyp1A1 mRNA. There were no differences in the biologicalactivity between these formulations. The lack of dose response fromFormulations 17, 21 and 22 suggests this upregulation has reached a maxor plateau that is likely achieved with formulations containing 0.5%3,5-Dihydroxy-4-isopropyl-trans-stilbene or below. These data confirmthe concentrations quantified in the in vitro skin penetration studiesare bioavailable and capable of engaging targets within human skin. Whathas been found is that this assay does not provide statisticallysignificant differences between formulations and/or concentrations ofactive in the formulations.

Example 13—Systemic Exposure and Skin Concentrations of3,5-Dihydroxy-4-Isopropyl-Trans-Stilbene Following 7 Day TopicalAdministration to Gottingen Minipigs

To assess tissue concentrations and systemic exposure, a toxicokineticsstudy in Gottingen minipigs was conducted with repeat topicaladministration of 3,5-Dihydroxy-4-isopropyl-trans-stilbene over 7 days.To compare systemic exposure to local skin tissue levels, tissuebiopsies were collected, sectioned, and analyzed for active ingredientand compared to plasma concentrations on Day 1 and Day 7. A similarmethodology for skin biopsies in minipigs is described in the literaturesuch as by Mitra A, et al., Use of Minipig Skin Biopsy Model as anInnovative Tool to Design Topical Formulation to Achieve DesiredPharmacokinetics in Humans. J Pharm Sci. 2015, Feb. 17.

Formulation 22 (2% of active ingredient) and Formulation 12 (2.0%, e.g.formulation 14) were applied to the non-abraded skin of minipigs (3males/group) at a dose of 2% daily (for a period of approximately 23hours) for 7 days. Dermal application sites for these groups were 10% ofthe total body surface area. The dose weight was 2 g/kg/day, asdetermined by formulation feasibility testing conducted prior to thestart of dosing (the appropriate vehicle was applied to 10% of the totalbody surface area of the first minipig in each of the aforementioneddose groups for approximately 23 hours). Hair was removed from the backand flanks of each animal on Days 1, 7 and 14, and as needed during thestudy. Application sites were semi-occluded with gauze patches held inplace with tape and tubular netting. At the end of the exposure period,the netting and patches were removed, and all sites were wiped with warmreverse osmosis-treated water and cotton gauze.

The following endpoints/parameters were evaluated: clinicalobservations, dermal irritation (scored using the Draize method, bodyweights, and macroscopic and microscopic observations (treated anduntreated skin). Toxicokinetic evaluation was performed on samplescollected on Days 1 and 7 for plasma and skin concentrations.

On Day 7, the minipigs were euthanized and the surface of the skin wascleaned through a combination of several wash steps including mildcleansers, solvents, shaving, and tape stripping to ensure residualformulation was removed from the surface of the skin. The skin was thenexcised and skin was placed epidermis side down on a clean surface. Skinbiopsies (8 mm) were harvested from the dosing areas, placed incryotubes, and immediately frozen until analysis. While still frozen,the hypodermis was removing using a razor blade and the upper section ofthe sample (epidermis and upper dermis, section from 0 to 500 μm) wasthen cut away from the dermis. Therefore, epidermis refers to the uppersection of the skin sample consisting of stratum corneum, epidermis, andupper dermis (approximately 500 μm) and dermis represents deeper dermis(approximately 1,500 μm meaning a cut of middle dermis to subcutaneousfat). The epidermis and dermis sections were then weighed andhomogenized in 1 ml of a 75:25 water:acetonitrile solution containing0.1% formic acid. The homogenate was further processed by proteinprecipitation using a solution of 100% acetonitrile with 0.1% formicacid and an internal standard (5 ng/ml). The supernatant from theprotein precipitation was passed through an Ostro 96 well plate toremove phospholipids.

Formulation 22 resulted in higher skin deposition of3,5-Dihydroxy-4-isopropyl-trans-stilbene, in the upper 500 μm and lower1,500 μm sections, compared to Formulation 12 (with 2% activeingredient, also referred to herein as Formulation 14). The increase inthe skin loading was observed on Day 1 and continued after 7 days ofrepeat dosing. This data suggests Formulation 22 has the capability ofchanging the skin microenvironment after a single application but canalso maintain this effect over longer dosing periods.

Surprisingly, the systemic exposure as measured by AUC on Day 1 and Day7 was lower for Formulation 22 compared to Formulation 12 (with 2%active ingredient, e.g. Formulation 14). The plasma concentrationsseemed to decrease further for Formulation 22 by Day 7, where the levelswere approximately 2.5 fold lower for Formulation 22 compared toFormulation 12 (with 2% active ingredient, e.g. Formulation 14). Thedata correlates with what was observed in the in vitro human skinpenetration studies where Formulation 22 showed higher skin depositionwith lower concentrations of 3,5-Dihydroxy-4-isopropyl-trans-stilbenedelivered to the receiving fluid. The combination of this data suggeststhat Formulation 22 is capable of delivering higher tissue amounts tothe target site, while minimizing systemic exposure.

Based on in vitro skin penetration flux and human data, predicted humanAUCs are expected be below 50 ng*h/mL, or below 42.5 ng*h/mL and thepredicted C_(max) is expected to be below 15 ng/ml or 12.5 ng/mL.

TABLE 10 AUC Cmax NOAEL Predicted Margin of NOAEL Predicted Margin ofNonclinical Study (ng · h/mL) (ng · h/mL) safety (ng/mL) (ng/mL) safetyDermal 99 42.5 2 7.13 12.5 <1 4% cream, BID, Minipig, 13 weeksSubcutaneous 99 42.5 2 31.6 12.5 2.5 3 mg/kg/day, Rat, 13 weeks

Based on in vivo minipig data and human data, the predicted human AUCsare expected to be below 30.0 ng*h/mL, or below 23.5 ng*h/mL. Based onin vivo minipig data and human data, the predicted C_(max) is expectedto be below 15 ng/ml or below 11.3 ng/mL.

Based now upon limited human data, human AUCs (0-8h) are expected to bebelow 16.0 ng*h/mL, or below 14 ng*h/mL, or below 11 ng*h/mL. In anotherembodiment, the C_(max) is expected to be below 5 ng/ml, or below 4ng/ml, or below 3 ng/ml.

TABLE 11 AUC Cmax NOAEL Predicted Margin of NOAEL Predicted Margin ofNonclinical Study (ng · h/mL) (ng · h/mL) safety (ng/mL) (ng/mL) safetyDermal 99 23.5 4 7.13* 11.3 ~1 4% cream, BID, Minipig, 13 weeksSubcutaneous 99 23.5 4 31.6 11.3 3 3 mg/kg/day, Rat, 13 weeks

Example 14—Systemic Exposure and Skin Concentrations of3,5-Dihydroxy-4-isopropyl-trans-stilbene Following 28 Day TopicalAdministration to Gottingen Minipigs

The 7 day topical administration of3,5-Dihydroxy-4-isopropyl-trans-stilbene in Formulation 22 showedsignificant concentrations of 3,5-Dihydroxy-4-isopropyl-trans-stilbenein the skin of Gottingen minipigs. The systemic levels from this studydecreased from Day 1 to Day 7, suggesting Formulation 22 is capable ofdelivering higher tissue amounts to the target site, while minimizingsystemic exposure. To see if this trend would continue over a longerdosing period, a repeat dosing of topical administration of3,5-Dihydroxy-4-isopropyl-trans-stilbene over 28 days was conducted toassess the tissue concentrations, dermal toxicity, dermal irritancy andtoxicokinetics from Formulation 22.

The formulations were administered as a twice daily (10±1 hours apart)topical application to the dorsal skin (˜10% of total body surface area)of Gottingen minipigs (3/sex/group) for 28 days and the dermal toxicity,dermal irritancy and of 3,5-Dihydroxy-4-isopropyl-trans-stilbene wasdetermined. The initial daily doses were 0 (vehicle), 10, 20 or 60mg/kg/day 3,5-Dihydroxy-4-isopropyl-trans-stilbene (concentrations at 0,0.5, 1.0 and 3.0% w/w, respectively) at a dose formulation weight of 1g/kg/dose (2 g/kg/day). Following dose application on each dosing day,the dose sites were semi-occluded for approximately 20±1 hours from thefirst dose and then gently washed before the next dose was applied.

TABLE 12 Mean Plasma and Skin Toxicokinetic Parameters Following TwiceDaily Dermal Administration of 3,5-Dihydroxy-4-isopropyl-trans-stilbenein Formulation 22 to Male and Female Gottingen Minipigs Male FemaleDaily Dose (mg/kg/day)^(a) 0 10 20 60 0 10 20 60 Numbers of Animals: 3 33 3 3 3 3 3 AUC_((0-t)) (ng · h/mL) Day 1 NA NA NA NR NA NR NA NR Day 28NA NA NA NR NA NR NA 4.84 C_(max) (ng/mL) Day 1 NA NA NA 0.376 NA NR NA0.408 Day 28 NA NA NA 0.845 NA 0.395 NA 0.830 Skin Concentration (Day29; ng/g) Epidermis/Upper Dermis — 4830 3950 10000 — 2540 2270 6530Lower Dermis — 166 615 3660 — NQ 305 3.04 NA: Not Applicable. NR: Notreported due to the limited data; NQ: Not quantifiable, theconcentration below the limit of quantitation (0.300 ng/mL for plasmaand 0.25 ng/mL for skin) ^(a)Doses expressed in terms of parentcompound.

On Days 1 and 28, 3,5-Dihydroxy-4-isopropyl-trans-stilbene was notquantifiable in plasma at 5 and 10 mg/kg/dose (10 and 20 mg/kg/day)except for 2 time points on Day 28 (3 and 24 hours post first dose)which had 1 concentration value at each time point for females at 5mg/kg/dose (10 mg/kg/day). At 30 mg/kg/dose (60 mg/kg/day),3,5-Dihydroxy-4-isopropyl-trans-stilbene was quantifiable in plasma upto 3 hours after dosing (either first or second dose) on Days 1 and 28.

The T_(max) values ranged from 1 to 3 hours post-dose (either first orsecond dose) on Days 1 and 28 at the 60 mg/kg/day dose level. TheC_(max) values ranged from 0.306 to 1.81 ng/ml for males and females.Generally, AUC_(0·t) could not be reported due to the majority of theconcentrations values being lower than the limit of quantification.

3,5-Dihydroxy-4-isopropyl-trans-stilbene concentrations were generallyhigher in the epidermis/upper dermis of both males and females thanthose in the lower dermis. The gender-averaged individual animal skinconcentrations at necropsy were highest in the 60 mg/kg/day group at8265 ng/g in the epidermis/upper dermis and 1830 ng/g in the lowerdermis. Comparison of the concentrations in the skin to those in theplasma could not be assessed since the Day 28 24 hour plasmaconcentrations were below the limit of quantification.

All animals survived to their scheduled necropsy. There was no testarticle-related dermal irritation based on dermal evaluation of the dosesite. There was no systemic toxicity based on clinical observations,cardiovascular (ECG) and ophthalmoscopic evaluations, body weight, foodconsumption, clinical pathology and post-mortem evaluations (organweights, macroscopic and microscopic pathology). Thus, one embodiment ofthe invention is a non-irritating or reduced irritating pharmaceuticalcomposition comprising 3,5-Dihydroxy-4-isopropyl-trans-stilbene or apharmaceutically acceptable salt thereof, as compared to a formulationhaving a composition of 1 or 12 (with comparable % w/w active).

In conclusion, following twice daily topical administration of3,5-Dihydroxy-4-isopropyl-trans-stilbene at doses of 0 (vehicle), 0.5,1.0 and 3.0% w/w (animal study) in the present inventive formulationsdescribed in Example 7 (10, 20 mg/kg/day) and Example 8 (60 mg/kg/day,respectively) onto ˜10% of total body surface area of minipigs(n=3/sex/group) for 28 days, resulted in no dermal irritation orsystemic toxicity. Therefore the “No Observed Adverse Effect Level”(NOAEL) for dermal irritation or systemic toxicity was 3% (w/w) or 60mg/kg/day, the highest dose tested.3,5-Dihydroxy-4-isopropyl-trans-stilbene achieved a peak averageconcentration of 8265 ng/g in the skin (epidermis/upper dermis) in the60 mg/kg/day group while systemic exposures were relatively much loweror often below the limit of quantitation in all treatment groups.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The above description fully discloses the invention including preferredembodiments thereof. Modifications and improvements of the embodimentsspecifically disclosed herein are within the scope of the followingclaims. Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, utilize the presentinvention to its fullest extent. Therefore, the Examples herein are tobe construed as merely illustrative and not a limitation of the scope ofthe present invention in any way. The embodiments of the invention inwhich an exclusive property or privilege is claimed are defined asfollows.

What is claimed is:
 1. A method of improving residency time in the skinof a patient in need thereof with a composition containing the activeingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or apharmaceutically acceptable salt thereof in use in a patient, the methodcomprising administering to said patient a homogenous emulsioncomposition comprising the active ingredient, an oil phase, a waterphase, a surfactant, and an antioxidant, and optionally wherein theemulsion composition is compared to that of Formulation 1 or 12.